Role Of Mononuclear Phagocytes Research Articles

The Role of Mononuclear Phagocytes in the Testes and Epididymis

The mononuclear phagocytic system (MPS) is the primary innate immune cell group in male reproductive tissues, maintaining the balance of pro-inflammatory and immune tolerance. This article aims to outline the role of mononuclear macrophages in the immune balance of the testes and epididymis, and to understand the inner immune regulation mechanism. A review of pertinent publications was performed using the PubMed and Google Scholar databases on all articles published prior to January 2021. Search terms were based on the following keywords: 'MPS', 'mononuclear phagocytes', 'testes', 'epididymis', 'macrophage', 'Mφ', 'dendritic cell', 'DC', 'TLR', 'immune', 'inflammation', and 'polarization'. Additionally, reference lists of primary and review articles were reviewed for other publications of relevance. This review concluded that MPS exhibits a precise balance in the male reproductive system. In the testes, MPS cells are mainly suppressed subtypes (M2 and cDC2) under physiological conditions, which maintain the local immune tolerance. Under pathological conditions, MPS cells will transform into M1 and cDC1, producing various cytokines, and will activate T cell specific immunity as defense to foreign pathogens or self-antigens. In the epididymis, MPS cells vary in the different segments, which express immune tolerance in the caput and pro-inflammatory condition in the cauda. Collectively, MPS is the control point for maintaining the immune tolerance of the testes and epididymis as well as for eliminating pathogens.

P96: The role of mononuclear phagocytes in the testis and epididymis

P96: The role of mononuclear phagocytes in the testis and epididymis

Subsets of mononuclear phagocytes are enriched in the inflamed colons of patients with IBD

BackgroundMyeloid cells, especially mononuclear phagocytes, which include monocytes, macrophages and dendritic cells (DC), play vital roles in innate immunity, and in the initiation and maintenance of adaptive immunity. While T cell-associated activation pathways and cytokines have been identified and evaluated in inflammatory bowel disease (IBD) patients (Neurath, Nat Rev Gastroenterol Hepatol 14:269–78, 1989), the role of mononuclear phagocytes are less understood. Recent reports support the crucial role of DC subsets in the development of acute colitis models (Arimura et al., Mucosal Immunol 10:957–70, 2017), and suggest they may contribute to the pathogenesis of ulcerative colitis (UC) by inducing Th1/Th2/Th17 responses (Matsuno et al., Inflamm Bowel Dis 23:1524–34, 2017).ResultsWe performed in silico analysis and evaluated the enrichment of immune cells, with a focus on mononuclear phagocytes in IBD patient colonic biopsies. Samples were from different gut locations, with different levels of disease severity, and with treatment response to current therapies. We observe enrichment of monocytes, M1 macrophages, activated DCs (aDCs) and plasmacytoid dendritic cells (pDCs) in inflamed tissues from various gut locations. This enrichment correlates with disease severity. Additionally, the same mononuclear phagocytes subsets are among the top enriched cell types in both infliximab and vedolizumab treatment non-responder samples. We further investigated the enrichment of selected DC and monocyte subsets based on gene signatures derived from a DC- and monocyte-focused single cell RNA-seq (scRNA-seq) study (Villani et al., Science 356:eaah4573, 2017), and verified enrichment in both inflamed tissues and those with treatment resistance. Moreover, we validated an increased mononuclear phagocyte subset abundance in a Dextran Sulphate Sodium (DSS) induced colitis model in C57Bl/6 mice representative of chronic inflammation.ConclusionsWe conducted an extensive analysis of immune cell populations in IBD patient colonic samples and identified enriched subsets of monocytes, macrophages and dendritic cells in inflamed tissues. Understanding how they interact with other immune cells and other cells in the colonic microenvironment such as epithelial and stromal cells will help us to delineate disease pathogenesis.

The role of mononuclear phagocytes in Ebola virus infection.

The filovirus, Zaire Ebolavirus (EBOV), infects tissue macrophages (Mϕs) and dendritic cells (DCs) early during infection. Viral infection of both cells types is highly productive, leading to increased viral load. However, virus infection of these two cell types results in different consequences for cellular function. Infection of Mϕs stimulates the production of proinflammatory and immunomodulatory cytokines and chemokines, leading to the production of a cytokine storm, while simultaneously increasing tissue factor production and thus facilitating disseminated intravascular coagulation. In contrast, EBOV infection of DCs blocks DC maturation and antigen presentation rendering these cells unable to communicate with adaptive immune response elements. Details of the known interactions of these cells with EBOV are reviewed here. We also identify a number of unanswered questions that remain about interactions of filoviruses with these cells.

The Good, the Bad, and the Ugly of Dendritic Cells during Prion Disease.

Prions are a unique group of proteinaceous pathogens which cause neurodegenerative disease and can be transmitted by a variety of exposure routes. After peripheral exposure, the accumulation and replication of prions within secondary lymphoid organs are obligatory for their efficient spread from the periphery to the brain where they ultimately cause neurodegeneration and death. Mononuclear phagocytes (MNP) are a heterogeneous population of dendritic cells (DC) and macrophages. These cells are abundant throughout the body and display a diverse range of roles based on their anatomical locations. For example, some MNP are strategically situated to provide a first line of defence against pathogens by phagocytosing and destroying them. Conventional DC are potent antigen presenting cells and migrate via the lymphatics to the draining lymphoid tissue where they present the antigens to lymphocytes. The diverse roles of MNP are also reflected in various ways in which they interact with prions and in doing so impact on disease pathogenesis. Indeed, some studies suggest that prions exploit conventional DC to infect the host. Here we review our current understanding of the influence of MNP in the pathogenesis of the acquired prion diseases with particular emphasis on the role of conventional DC.

Abstract 60: The Role of Mononuclear Phagocytes in Pressure Overload Heart Failure

We previously reported that chronic ischemic HF induced by coronary ligation results in an exacerbated pro-inflammatory cell profile in the systemic circulation, spleen, and failing heart. In addition, this pro-inflammatory cell profile was strongly influenced by the cardiosplenic axis; however, the role of this axis in other etiologies of HF is unknown. Immune cells infiltrate the heart early (1-4 weeks) after pressure-overload injury, but it is unknown whether these cells persist and are of pathological import during chronic pressure-overload HF. We hypothesized that phenotypic changes in mononuclear phagocytes are necessary for the transition from compensatory hypertrophy to chronic HF during sustained pressure-overload, and that inhibition of myocardial immune cell infiltration would ameliorate this progression. Pressure-overload was induced by transverse aortic constriction (TAC) in wild-type (WT) C57BL/6 mice, and in macrophage Fas-induced apoptosis (MAFIA) Tg mice, which allows ablation of c-fms expressing cells upon administration of the AP20187 dimerizer. Compared to sham mice, TAC mice developed progressive cardiac dysfunction beginning at 2 w with significantly (p<0.05) reduced LVEF (59 ± 10 vs 67 ± 3 %), increased left atrial size (2.29 ± 0.1 vs 2.04 ± 0.1 mm), and increased E/E’ Doppler ratio (31.8 ± 6 vs 24.0 ± 3). Circulating CD11b+Lineage- monocytes were elevated in TAC mice at 2 w (1.7 ± 0.2 vs 1.0 ± 0.1 %, p<0.05); however, these levels normalized by 8 w. Moreover, at 8 w, no significant differences in the levels of splenic and cardiac mononuclear phagocytes were seen between TAC and sham mice. Systemic ablation of mononuclear phagocytes beginning 2 w after TAC in MAFIA AP20187-treated mice did not rescue cardiac function or delay HF progression compared to TAC MAFIA vehicle-treated mice over the course of 16 w (LVEF 43 ± 18 vs 45 ± 18 %). We conclude that in contrast to chronic ischemic HF, inflammatory cell-mediated cardiac injury does not have primacy in chronic non-ischemic HF induced by pressure-overload. These findings highlight the importance of the index injury in regard to immune cell activation in HF, and suggest that therapeutic immunomodulatory approaches may not be equivalent across the various etiologies of this disease.

Remodeling of the Mononuclear Phagocyte Network Underlies Chronic Inflammation and Disease Progression in Heart Failure

Rationale: The role of mononuclear phagocytes in chronic heart failure (HF) is unknown. Objective: Our aim was to delineate monocyte, macrophage, and dendritic cell trafficking in HF and define the contribution of the spleen to cardiac remodeling. Methods and Results: We evaluated C57Bl/6 mice with chronic HF 8 weeks after coronary ligation. As compared with sham-operated controls, HF mice exhibited: (1) increased proinflammatory CD11b + F4/80 + CD206 − macrophages and CD11b + F4/80 + Gr-1 hi monocytes in the heart and peripheral blood, respectively, and reduced CD11b + F4/80 + Gr-1 hi monocytes in the spleen; (2) significantly increased CD11c + B220 − classical dendritic cells and CD11c +/low B220 + plasmacytoid dendritic cells in both the heart and spleen, and increased classic dendritic cells and plasmacytoid dendritic cells in peripheral blood and bone marrow, respectively; (3) increased CD4 + helper and CD8 + cytotoxic T-cells in the spleen; and (4) profound splenic remodeling with abundant white pulp follicles, markedly increased size of the marginal zone and germinal centers, and increased expression of alarmins. Splenectomy in mice with established HF reversed pathological cardiac remodeling and inflammation. Splenocytes adoptively transferred from mice with HF, but not from sham-operated mice, homed to the heart and induced long-term left ventricular dilatation, dysfunction, and fibrosis in naive recipients. Recipient mice also exhibited monocyte activation and splenic remodeling similar to HF mice. Conclusions: Activation of mononuclear phagocytes is central to the progression of cardiac remodeling in HF, and heightened antigen processing in the spleen plays a critical role in this process. Splenocytes (presumably splenic monocytes and dendritic cells) promote immune-mediated injurious responses in the failing heart and retain this memory on adoptive transfer.

Virus-encoded TLR ligands reveal divergent functional responses of mononuclear phagocytes in pathogenic simian immunodeficiency virus infection.

The role of mononuclear phagocytes in the pathogenesis or control of HIV infection is unclear. In this study, we monitored the dynamics and function of dendritic cells (DC) and monocytes/macrophages in rhesus macaques acutely infected with pathogenic SIVmac251 with and without antiretroviral therapy (ART). SIV infection was associated with monocyte mobilization and recruitment of plasmacytoid DC (pDC) and macrophages to lymph nodes, which did not occur with ART treatment. SIVmac251 single-stranded RNA encoded several uridine-rich sequences that were potent TLR7/8 ligands in mononuclear phagocytes of naive animals, stimulating myeloid DC (mDC) and monocytes to produce TNF-α and pDC and macrophages to produce both TNF-α and IFN-α. Following SIV infection, pDC and monocytes/macrophages rapidly became hyporesponsive to stimulation with SIV-encoded TLR ligands and influenza virus, a condition that was reversed by ART. The loss of pDC and macrophage function was associated with a profound but transient block in the capacity of lymph node cells to secrete IFN-α upon stimulation. In contrast to pDC and monocytes/macrophages, mDC increased TNF-α production in response to stimulation following acute infection. Moreover, SIV-infected rhesus macaques with stable infection had increased mDC responsiveness to SIV-encoded TLR ligands and influenza virus at set point, whereas animals that progressed rapidly to AIDS had reduced mDC responsiveness. These findings indicate that SIV encodes immunostimulatory TLR ligands and that pDC, mDC, and monocytes/macrophages respond to these ligands differently as a function of SIV infection. The data also suggest that increased responsiveness of mDC to stimulation following SIV infection may be beneficial to the host.

New Roles for Mononuclear Phagocytes in Cancer Biology

The primary focus in the pathogenesis and treatment of human malignancies has been the tumor cell. However, the biologic properties of a malignancy are not all intrinsically determined. Interactions between heterogeneous cell populations influence the growth and survival of both normal and malignant cells. Studies defining the origin of endothelial cells involved in tumor angiogenesis first demonstrated the contributions of normal cellular environment. Recently, the mononuclear phagocyte lineage has been found to have biologically and clinically significant tumor enhancing and tumor suppressive effects. This article reviews the multiple roles of mononuclear phagocytes in cancer biology. A companion manuscript (J Pediatr Hematol Oncol. 2008, in press) describes the targeting of these cells for therapeutic benefit. Incorporating these strategies into future childhood cancer protocols could be an innovative approach for improving patient outcome.

Viral reservoirs, residual viremia, and the potential of highly active antiretroviral therapy to eradicate HIV infection

Although highly active antiretroviral therapy (HAART) can reduce HIV-1 viremia to levels that are below the limit of detection of clinical assays, the virus persists in reservoirs, and trace levels of free virions can be found in the plasma. Whether this residual viremia represents ongoing cycles of replication continuing despite HAART or simply the release of virus from stable reservoirs has been controversial. Here we summarize the evidence that HAART can stop ongoing cycles of replication. The evidence comes from a detailed analysis of the residual viremia, which shows it to be archival and nonevolving in character. In addition, new pharmacodynamic measures incorporating a previously ignored slope parameter have provided the first real indication of how well HAART actually suppresses viral replication in vivo. Together, these results argue that the ultimate theoretical potential of HAART to control viral replication has already been reached. Progress toward eradication of the infection will require novel approaches to target the stable reservoirs that persist even when viral replication is completely halted.

Inflammatory cytokine mRNA expression during early and persistent Helicobacter pylori infection in nonhuman primates.

The role of mononuclear phagocytes in orchestrating the host responses to Helicobacter pylori is inadequately understood. Therefore, gene expression for the monocyte/macrophage-derived cytokines interleukin (IL)-1beta, IL-6, and tumor necrosis factor (TNF)-alpha was determined before and during H. pylori infection of rhesus monkeys by use of a highly sensitive quantitative reverse transcriptase polymerase chain reaction. The numbers of molecules of IL-1beta, IL-6, and TNF-alpha mRNA in gastric tissue during early infection (7 weeks) significantly exceeded the preinfection numbers (P<.03). Moreover, the numbers of IL-1beta, IL-6, and TNF-alpha mRNA molecules in persistently infected animals (6 years) also were elevated compared with preinfection numbers (P<.02, P=.03, P=.16, respectively). Cytokine gene expression coincided with progressive H. pylori gastritis, confirmed by increased gastritis scores over preinfection scores (P<.005). These findings provide quantitative evidence that H. pylori induces local gene expression of monocyte/macrophage-derived inflammatory cytokines and evokes an innate response in gastric tissue of nonhuman primates.

The Role of Thymus-Dependent T Cells in Hexachlorobenzene-Induced Inflammatory Skin and Lung Lesions

The involvement of thymus-dependent T cells in the inflammatory skin and lung lesions and spleen effects induced by hexachlorobenzene (HCB) was investigated by using genetically athymic and euthymic WAG/Rij rats and Brown Norway (BN) rats with or without depletion of T cells by adult thymectomy, lethal irradiation, and bone marrow reconstitution. Rats were exposed to diets with no supplementation or diets supplemented with 150 or 450 mg HCB per kg diet for 4 (BN) or 6 (WAG/Rij) weeks. Skin lesion development and body weight gains were assessed during exposure and spleen and liver weights as well as histopathologic changes in skin, lung, and spleen were assessed after exposure. Oral HCB exposure of athymic and euthymic rats of both rat strains resulted in a dose-dependent increase of relative liver weight at doses of 150 and 450 mg/kg HCB and increased relative spleen weights at a dose of 450 mg/kg. HCB exposure of both strains further resulted in inflammatory changes in skin, lungs, and splenic red pulp independent of the T cell status except for skin lesions in the BN strain. HCB-exposed T cell-competent BN rats showed faster skin lesion development than the T cell-depleted rats, although qualitatively and quantitatively similar skin pathology was observed at the end of the 4-week exposure in both groups. In the WAG/Rij strain skin lesions could not be comparatively assessed due to preexistent inflammatory skin pathology in the nude rats. This study showed that thymus-derived T cells are not required for the induction of skin and lung pathology and splenic changes by HCB and therefore it is suggested that HCB acts differently from many allergenic and autoimmunogenic low molecular weight compounds that trigger pathology via thymus-dependent mechanisms. A role for mononuclear phagocytes and, in BN rats, eosinophilic granulocytes, in the HCB-induced pathology is suggested since these cells were prominently present in the HCB-induced lesions.

Exacerbation of murine Pneumocystis carinii infection by adenoviral-mediated gene transfer of a TNF inhibitor.

The role of mononuclear phagocytes and their cytokine products in host defense against Pneumocystis carinii (PC) remains unclear. The cytokine tumor necrosis factor (TNF) has been proposed as critical for host defense against this pathogen. To investigate the role of this cytokine in PC infection, we treated immunocompetent mice (CD4+) or mice depleted of CD4 lymphocytes (CD4-) with a recombinant adenovirus encoding a TNF inhibitor gene (AdTNF-R). AdTNF-R treated CD4+ animals displayed delayed clearance of PC after intratracheal inoculation, whereas AdTNF-R treated CD4 animals developed more severe chronic infection. Moreover, AdTNF-R treated CD4- animals, in contrast to control CD4- mice, failed to show any interleukin-6 (IL-6) gene induction in the lung after PC challenge. The results firmly implicate TNF in host defense against PC, and support a role for TNF in orchestrating the intrapulmonary cytokine cascade in PC infection.

Analysis of the initiation period of spontaneous autoimmune thyroiditis (SAT) in obese strain (OS) of chickens.

The early, predictable, onset of spontaneous autoimmune thyroiditis (SAT) in Obese strain (OS) chickens provides a unique opportunity to analyse the mechanisms initiating autoimmunity which is virtually impossible to obtain in humans. In this study we focused on the respective roles of viruses and macrophages in the initiation of SAT. To analyse viruses, leukosis virus-free OS chickens were bred over three generations and reared under gnotobiotic conditions. By 2 weeks of age there were no differences in the levels of thyroid mononuclear cell infiltration between these and control animals. The role of mononuclear phagocytes in SAT was determined by their depletion via injecting newborn OS chicks with silica or carrageenan and dichloro-methylene diphosphonate encapsulated into liposomes. Although this treatment did not substantially change the amount of macrophages in primary lymphoid organs or blood, there was destruction of splenic architecture and, most importantly, mononuclear cell infiltration of the thyroids was significantly lower compared to controls. The role of activated macrophages in SAT is discussed.

The neuroimmune mechanisms for HIV-tπ dementia: The role of mononuclear phagocytes and astrocytes in virus-related brain disease

The neuroimmune mechanisms for HIV-tπ dementia: The role of mononuclear phagocytes and astrocytes in virus-related brain disease

Immunophenotypic Analysis of Mononuclear Phagocyte Antigens in the Arthritic Synovium of the Hip Joint

The antigenic phenotype of lining and subintimal mononuclear phagocytes (MPs) of the synovium in osteoarthritis (OA) and rheumatoid arthritis (RA) was characterised, using monoclonal antibodies directed against a range of monocyte/macroph-ageassociated antigens, in order to determine the role of MPs in the pathobiology of OA and RA of the hip. A major proportion of synovial lining cells (SLCs) and subintimal cells in RA and OA consisted of CD68 positive MPs which expressed a wide range of macrophage-associated antigens. The monocyte marker, CD14, was downregulated on SLCs in RA while OA and early markers of MP activation predominated in the OA synovium which was independent of the level of inflammation. In contrast, synovial MPs in RA showed increased expression of activation, maturation and functional antigens such as CD11a, CD11b, CD11c, CD16, CD32, CD54, CD64. Moreover, MP recruitment did not correlate with the degree of lymphocytic infiltration in RA. Thus, synovial MPs in RA are rapidly and fully activated with upregulation of activation, differentiation, and functional antigens occurring in situ. There was also no difference in antigenic phenotype of synovial MPs in inflammatory and non-inflammatory OA.

The kinetics and morphological characteristics of the macrophage-microglial response to kainic acid-induced neuronal degeneration

Outside the nervous system myelomonocytic cells are known to play an important role in the inflammatory response and tissue repair after injury. In this study we have examined the myelomonocytic response to neuronal destruction following unilateral injection of the excitotoxin kainic acid into the mouse hippocampus. Intrahippocampal injection of kainate induces rapid, synchronous neuronal death. There is no neutrophil recruitment and a delay of at least 48 h before macrophage-microglial cell numbers increase. The microglial reaction in the injected hippocampus consists of altered morphology, a 6–9-fold increase in mononuclear phagocyte cell numbers and enhanced expression of the macrophage-specific plasma membrane antigen, F4/80, assessed immunohistochemically and by Western blotting. Microglia also respond at distant sites related to the projection pathway and terminals of killed pyramidal cells but the reaction varies in cell numbers, kinetics and morphology. The absence of neutrophil recruitment and the delay in an increase in macrophage or microglial cells shows that the CNS differs from other sites in the body with regard to the kinetics and nature of the myelomonocytic cell inflammatory response. The role of mononuclear phagocytes in tissue repair in the CNS remains to be defined.

Role of Mononuclear Phagocytes in the Pathogenesis of Human Immunodeficiency Virus Infection

We have presented evidence in this review for the following: (a) Macrophages are likely the first cell infected by HIV. Recovery of HIV from macrophages has been documented in the early stages of infection in which virus isolation in T cells is unsuccessful and detectable levels of antibodies against HIV are absent. (b) Macrophages are major reservoirs for HIV during all stages of infection. Unlike the lytic infection of T cells, HIV-infected macrophages show little or no virus-induced cytopathic effects. HIV-infected macrophages persist in tissue for extended periods of time (months) with large numbers of infectious particles contained within intracytoplasmic vacuoles. (c) Macrophages are a vector for the spread of infection to different tissues within the patient and between individuals. Several studies suggest a "Trojan horse" role for HIV-infected macrophages in the dissemination of infectious particles. The predominant cell in most bodily fluids (alveolar fluid, colostrum, semen, vaginal secretions) is the macrophage. In semen, for example, the numbers of macrophages exceed those of lymphocytes by more than 20-fold. (d) Macrophages are major regulatory cells that control the pace and intensity of disease progression in HIV infection. Macrophage secretory products are implicated in the pathogenesis of CNS disease and in control of viral latency in HIV-infected T cells. This litany of events in which macrophages participate in HIV-infection in humans parallels similar observations in such animal lentivirus infections as visna-maedi or caprine arthritis-encephalitis viruses. HIV interacts with monocytes differently than with T cells. Understanding this interaction may more clearly define both the pathogenesis of HIV disease and strategies for therapeutic intervention.

The role of mononuclear phagocytes in wound healing after traumatic injury to adult mammalian brain

We monitor cellular responses to a penetrating wound in the cerebral cortex of adult rat during the first weeks after injury. Two classes of activated mononuclear phagocytes containing acetylated low-density lipoprotein (ac-LDL) receptors appear within hours at the wound site. One type of cell surrounding the lesion edge had thin, delicate processes and is identical in appearance to ramified microglia found in developing brain. Within the lesion, round cells are recognized as blood-borne macrophages when labeled by intravenous injection of carbon particles. Thus, both process-bearing reactive microglia and invading macrophages respond to brain trauma. The greatest number of ac-LDL(+) or nonspecific esterase(+) mononuclear phagocytes appears 2 days after injury within the wound site and are associated with a peak production of the cytokine interleukin-1 (IL-1). Because intracerebral infusion of IL-1 is known to stimulate astrogliosis and neovascularization (Giulian et al., 1988), we examine the time course of injury-induced reactive astrogliosis and angiogenesis. A 5-fold increase in the number of reactive astroglia is found at 3 d and a marked neovascularization at 5 d after injury. During the first week, mononuclear phagocytes engulf particles and clear them from the wound site either by migrating to the brain surface or by entering newly formed brain vasculature. To investigate further the role of reactive brain mononuclear phagocytes in CNS injury, we use drugs to inhibit trauma-induced inflammation. When applied in vivo, chloroquine or colchicine reduce the number of mononuclear phagocytes in damaged brain, help to block reactive astrogliosis and neovascularization, and slow the rate of debris clearance from sites of traumatic injury. In contrast, the glucocorticoid dexamethasone neither reduces the number of brain inflammatory cells nor hampers such responses as phagocytosis, astrogliosis, neovascularization, or debris clearance in vivo. Our observations show that mononuclear phagocytes play a major role in wound healing after CNS trauma with some events controlled by secretion of cytokines. Moreover, certain classes of immunosuppressive drugs may be useful in the treatment of acute brain injury.

Role of mononuclear phagocytes in elimination of Plasmodium chabaudi AS infection

The role of mononuclear phagocytes in acquired immunity resulting in the intraerythrocytic destruction and elimination of malarial parasites was investigated in the murine model of infection with Plasmodium chabaudi AS. Mice were treated 1 day before or 6 days after infection with agents which either result in augmentation or activation of the non-specific, microbicidal effector function of mononuclear phagocytes or in depletion of cells of this lineage. To examine the effect of agents which activate mononuclear phagocytes. A/J mice, which are susceptible to P. chabaudi AS and exhibit fulminant parasitaemia and death within 10 days of intraperitoneal infection with 10(6) P-RBC, were treated intravenously with muramyl dipeptide (MDP) or liposome-encapsulated MDP-glycerol dipalmitate (MDP-GDP). Treatment administered 1 day before infection was ineffective. Treatment on day 6 post-infection with liposome-encapsulated MDP-GDP (1 microgram) resulted in a significant decrease in parasitaemia on day 8 and survival, while treatment with free MDP (100 micrograms) resulted only in a significant decrease in parasitaemia. To examine the effect of depletion of mononuclear phagocytes, C57BL/6 mice, which are resistant to P. chabaudi AS infection and eliminate the parasite by 4 weeks, were treated intravenously with 3 mg silica. Silica administered 1 day before or 6 days post-infection abrogated resistance resulting in a delay in elimination of the parasite and host mortality. Treatment on day 6 was more effective, with death by day 13 post-infection of 70% of the normally resistant C57BL/6 mice which exhibited fulminant parasitaemia levels. These results thus provide in-vivo evidence that mononuclear phagocytes play a critical role in the elimination of infection with the murine malaria species P. chabaudi AS. Furthermore, these results suggest that the time of administration of agents which alter mononuclear phagocyte function may be important in determining their effect on host antimalarial defences.