Therapeutic Strategy For Inflammatory Diseases Research Articles

Erythrocyte-Like Mesoporous PDA@CeO2 Nanozyme with Dual Drugs for Periodontitis Treatment.

Periodontitis is a chronic oral inflammatory disease with the characteristic of excess oxidative stress in the inflammatory site, dramatically decreasing the quality of life. Studies show that nanozymes can be ideal candidates for ROS scavenging in periodontitis. Here, we design a multipath anti-inflammatory mesoporous polydopamine@cerium oxide nanobowl (mPDA@CeO2 NB) with multienzyme mimicking properties, which combines the advantages of both CeO2 NP and mPDA NB for synergistically eliminating reactive oxygen species (ROS), including hydroxyl radical (•OH), hydrogen peroxide (H2O2), and superoxide (O2•-). Besides, the erythrocyte-like structure of mNBs makes them a facility for cell uptake, and the mesopores can load both hydrophobic and hydrophilic drugs for combined anti-inflammatory therapy. In vitro and in vivo experiments prove that the combination of CeO2 and mPDA can synergistically achieve multiple complementary ROS eliminations and suppression of ROS-induced inflammation. Moreover, the ROS regulation plus anti-inflammatory drugs in one mPDA@CeO2 NB prevents the progression of periodontitis in a mouse model. Therefore, the design of mPDA@CeO2 NB with these excellent properties provides a therapeutic strategy for inflammatory diseases.

From Bronchial Asthma to Tuberculosis: Unravelling the Cytokine-Macrophage Axis in Diverse Diseases

Cytokines, tiny proteins secreted by cells, play a critical role in mediating communication and interactions between cells. They also function as immunomodulating agents, adjusting immune responses. When released into the bloodstream or tissues, cytokines bind to specific receptors on target immune cells, triggering cellular responses. Cytokines are implicated in various diseases, including asthma, COPD, HIV infection, and multiple sclerosis. This review delves into the intricate interplay between cytokines and macrophages, focusing on their roles in inflammation and the immune response. Macrophages, which are scavenger cells of the immune system, exhibit remarkable heterogeneity, reside in diverse tissues, and play crucial roles in both innate and acquired immunity. They can be activated for proinflammatory or anti-inflammatory functions, contributing to tissue destruction or regeneration. Cytokines influence macrophage activation and polarization, impacting the inflammatory process. Dysregulated cytokine production and macrophage activation are observed in various diseases. For example, in asthma, an imbalance in macrophage phenotypes contributes to airway hyperresponsiveness. Understanding the complex interplay between cytokines and macrophages is crucial for developing novel therapeutic strategies for inflammatory diseases. Future research directions include utilizing humanized animal models, single-cell sequencing, and immunomodulatory therapies to further decipher the intricate roles of cytokines and macrophages in health and disease. Ultimately, elucidating these interactions holds immense potential for improving human health outcomes.

Telocytes and inflammation: A review.

Telocytes are a new type of interstitial cell with a diverse morphology and important functions, such as mechanical support, signal transduction, immune regulation, and tissue repair. In this paper, the origin and physiological and pathological functions of telocytes as well as their role in inflammation will be discussed, and the functions and targets of telocytes in inflammation will be fully reviewed, which may contribute to a new therapeutic strategy for inflammatory diseases in the future.

PLK1 inhibition dampens NLRP3 inflammasome-elicited response in inflammatory disease models.

Unabated activation of the NLR family pyrin domain-containing 3 (NLRP3) inflammasome is linked with the pathogenesis of various inflammatory disorders. Polo-like kinase 1 (PLK1) has been widely studied for its role in mitosis. Here, using both pharmacological and genetic approaches, we demonstrate that PLK1 promoted NLRP3 inflammasome activation at cell interphase. Using an unbiased proximity-dependent biotin identification (Bio-ID) screen for the PLK1 interactome in macrophages, we show an enhanced proximal association of NLRP3 with PLK1 upon NLRP3 inflammasome activation. We further confirmed the interaction between PLK1 and NLRP3 and identified the interacting domains. Mechanistically, we show that PLK1 orchestrated the microtubule-organizing center (MTOC) structure and NLRP3 subcellular positioning upon inflammasome activation. Treatment with a selective PLK1 kinase inhibitor suppressed IL-1β production in in vivo inflammatory models, including LPS-induced endotoxemia and monosodium urate-induced peritonitis in mice. Our results uncover a role of PLK1 in regulating NLRP3 inflammasome activation during interphase and identify pharmacological inhibition of PLK1 as a potential therapeutic strategy for inflammatory diseases with excessive NLRP3 inflammasome activation.

Extracellular vesicles from normal tissues orchestrate the homeostasis of macrophages and attenuate inflammatory injury of sepsis.

Extracellular vesicles (EVs) exist throughout our bodies. We recently revealed the important role of intracardiac EVs induced by myocardial ischemia/reperfusion on cardiac injury and dysfunction. However, the role of EVs isolated from normal tissues remains unclear. Here we found that EVs, derived from murine heart, lung, liver and kidney have similar effects on macrophages and regulate the inflammation, chemotaxis, and phagocytosis of macrophages. Interestingly, EV-treated macrophages showed LPS resistance with reduced expressions of inflammatory cytokines and enhanced phagocytic activity. Furthermore, we demonstrated that the protein content in EVs contributed to the activation of inflammation, while the RNA component mainly limited the excessive inflammatory response of macrophages to LPS. The enrichment of miRNAs, including miR-148a-3p, miR-1a-3p and miR-143-3p was confirmed in tissue EVs. These EV-enriched miRNAs contributed to the inflammation remission in LPS induced macrophages through multiple pathways, including STAT3, P65 and SAPK/JNK. Moreover, administration of both EVs and EV-educated macrophages attenuated septic injury and cytokine storm in murine CLP models. Taken together, the present study disclosed that EVs from normal tissues can orchestrate the homeostasis of macrophages and attenuate inflammatory injury of sepsis. Therefore, tissue derived EVs or their derivatives may serve as potential therapeutic strategies in inflammatory diseases.

The Role of NLRP3 Inflammasomes in Trained Immunity.

Inflammasomes are cytosolic multi-protein complexes that play an important role in the innate immune system, inducing cytokine maturation and pyroptosis. Trained immunity is the induction of memory in innate immune cells by epigenetic reprogramming due to repeated inflammatory stimuli that alter the inflammatory response and increase resistance to infection or disease. Although it is speculated that nucleotide-binding oligomerization domain (NOD), leucine-rich repeat (LRR), and the NLR family pyrin domain containing 3 (NLRP3) inflammasomes respond to various inflammatory stimuli and are associated with trained immunity, the exact relationship is still unclear. This paper aims to introduce data from recent research on the role of inflammasomes in trained immunity through cellular immunometabolic and epigenetic reprogramming. It also suggests a new therapeutic strategy for inflammatory diseases through the complementary regulation of inflammasomes and trained immunity.

Metabolic control from the endolysosome: lysosome-resident amino acid transporters open novel therapeutic possibilities.

Amino acid transporters are generally recognized as machinery that transport amino acids from the extracellular environment into the cytoplasm. Although their primary function is the uptake of amino acids to supply the cell with nutrients and energy, endolysosome-resident amino acid (EL-aa) transporters possess several unique functions in accordance with their localization in intracellular vesicular membranes. They play pivotal roles in the maintenance of metabolic homeostasis via direct involvement in the amino acid sensing pathway, which regulates the activity of mechanistic target of rapamycin complex 1 (mTORC1), a master regulator of cellular metabolism. Additionally, some EL-aa transporters contribute to the maintenance of dynamic homeostasis of endolysosomes, including the regulation of endolysosomal acidity, by carrying amino acids out of endolysosomes. In addition, EL-aa transporters act as a scaffold to gather signaling molecules and multiple enzymes to control cellular metabolism on the endolysosomal membrane. Among EL-aa transporters, solute carrier family 15 member 4 (SLC15A4) is preferentially expressed in immune cells, including macrophages, dendritic cells, and B cells, and plays a key role in the integration of metabolic and inflammatory signals. In this review, we summarize our recent findings on EL-aa transporter contributions to inflammatory and metabolic signaling in the endolysosomes of immune cells by focusing on the SLC15 family, including SLC15A4 and SLC15A3, and discuss their uniqueness and universality. We also discuss the potential of targeting these EL-aa transporters in immune cells for the development of novel therapeutic strategies for inflammatory diseases. Because these transporters are highly expressed in immune cells and significantly alter the functions of immune cells, targeting them would provide a great advantage in ensuring a wide safety margin.

P2Y6R: A Promising New Target in Inflammatory Diseases and Advances in its Antagonists.

P2Y receptors (P2YRs) are G protein-coupled receptors that are activated by extracellular nucleotides. The P2Y6 receptor (P2Y6R) is specifically activated by UDP, causing PKC activation and intracellular calcium ion release through the PLC pathway. Based on receptor tissue distribution and related pathways, several studies have reported that P2Y6R plays a physiological role in mediating inflammation, which suggests that P2Y6R could be a promising molecular target for the treatment of inflammatory diseases. In the past ten years, several P2Y6R antagonists have been discovered as new therapeutic strategies for inflammatory diseases. In this article, we systematically summarize the role of P2Y6R in inflammation and highlight the anti-inflammatory mechanism of a key P2Y6R antagonist, MRS2578. Insight into recent progress on the discovery of P2Y6R antagonists is also discussed.

Epigenetic regulation of chemokine (CC-motif) ligand 2 in inflammatory diseases.

Appropriate responses to inflammation are conducive to pathogen elimination and tissue repair, while uncontrolled inflammatory reactions are likely to result in the damage of tissues. Chemokine (CC-motif) Ligand 2 (CCL2) is the main chemokine and activator of monocytes, macrophages, and neutrophils. CCL2 played a key role in amplifying and accelerating the inflammatory cascade and is closely related to chronic non-controllable inflammation (cirrhosis, neuropathic pain, insulin resistance, atherosclerosis, deforming arthritis, ischemic injury, cancer, etc.). The crucial regulatory roles of CCL2 may provide potential targets for the treatment of inflammatory diseases. Therefore, we presented a review of the regulatory mechanisms of CCL2. Gene expression is largely affected by the state of chromatin. Different epigenetic modifications, including DNA methylation, post-translational modification of histones, histone variants, ATP-dependent chromatin remodelling, and non-coding RNA, could affect the 'open' or 'closed' state of DNA, and then significantly affect the expression of target genes. Since most epigenetic modifications are proven to be reversible, targeting the epigenetic mechanisms of CCL2 is expected to be a promising therapeutic strategy for inflammatory diseases. This review focuses on the epigenetic regulation of CCL2 in inflammatory diseases.

CGAS Mediates Inflammation by Polarizing Macrophages to M1 Phenotype via the mTORC1 Pathway.

Cyclic GMP-AMP synthase (cGAS), as a cytosolic DNA sensor, plays a crucial role in antiviral immunity, and its overactivation induces excess inflammation and tissue damage. Macrophage polarization is critically involved in inflammation; however, the role of cGAS in macrophage polarization during inflammation remains unclear. In this study, we demonstrated that cGAS was upregulated in the LPS-induced inflammatory response via the TLR4 pathway, and cGAS signaling was activated by mitochondria DNA in macrophages isolated from C57BL/6J mice. We further demonstrated that cGAS mediated inflammation by acting as a macrophage polarization switch, which promoted peritoneal macrophages and the bone marrow-derived macrophages to the inflammatory phenotype (M1) via the mitochondrial DNA-mTORC1 pathway. In vivo studies verified that deletion of Cgas alleviated sepsis-induced acute lung injury by promoting macrophages to shift from the M1 phenotype to the M2 phenotype. In conclusion, our study demonstrated that cGAS mediated inflammation by regulating macrophage polarization through the mTORC1 pathway, and it further provided a potential therapeutic strategy for inflammatory diseases, especially sepsis-induced acute lung injury.

Ceramide Nanoliposomes as Potential Therapeutic Reagents for Asthma.

Ceramides are an emerging class of anti-inflammatory lipids, and nanoscale ceramide-delivery systems are potential therapeutic strategies for inflammatory diseases. This study investigated the therapeutic effects of ceramide nanoliposomes (CNL) on type 2 inflammation-based asthma, induced by repeated ovalbumin (OVA) challenges. Asthmatic mice intratracheally treated with ceramide-free liposomes (Ghost) displayed typical airway remodeling including mucosal accumulation and subepithelial fibrosis, whereas, in CNL-treated mice, the degree of airway remodeling was significantly decreased. Compared to the Ghost group, CNL treatment unexpectedly failed to significantly influence formation of type 2 cytokines, including IL-5 and IL-13, known to facilitate pathogenic production of airway mucus predominantly comprising MUC5AC mucin. Interestingly, CNL treatment suppressed OVA-evoked hyperplasia of MUC5AC-generating goblet cells in the airways. This suggests that CNL suppressed goblet cell hyperplasia and airway mucosal accumulation independently of type 2 cytokine formation. Mechanistically, CNL treatment suppressed cell growth and EGF-induced activation of Akt, but not ERK1/2, in a human lung epithelial cell culture system recapitulating airway goblet cell hyperplasia. Taken together, CNL is suggested to have therapeutic effects on airway remodeling in allergic asthma by targeting goblet cell hyperplasia. These findings raise the potential of ceramide-based therapies for airway diseases, such as asthma.

Innate Immune Memory in Monocytes and Macrophages: The Potential Therapeutic Strategies for Atherosclerosis.

Atherosclerosis is a complex metabolic disease characterized by the dysfunction of lipid metabolism and chronic inflammation in the intimal space of the vessel. As the most abundant innate immune cells, monocyte-derived macrophages play a pivotal role in the inflammatory response, cholesterol metabolism, and foam cell formation. In recent decades, it has been demonstrated that monocytes and macrophages can establish innate immune memory (also termed trained immunity) via endogenous and exogenous atherogenic stimuli and exhibit a long-lasting proinflammatory phenotype. The important cellular metabolism processes, including glycolysis, oxidative phosphorylation (OXPHOS), the tricarboxylic acid (TCA) cycle, fatty acid synthesis, and cholesterol synthesis, are reprogrammed. Trained monocytes/macrophages with innate immune memory can be persistently hyperactivated and can undergo extensive epigenetic rewiring, which contributes to the pathophysiological development of atherosclerosis via increased proinflammatory cytokine production and lipid accumulation. Here, we provide an overview of the regulation of cellular metabolic processes and epigenetic modifications of innate immune memory in monocytes/macrophages as well as the potential endogenous and exogenous stimulations involved in the progression of atherosclerosis that have been reported recently. These elucidations might be beneficial for further understanding innate immune memory and the development of therapeutic strategies for inflammatory diseases and atherosclerosis.

Osteocalcin Alleviates Lipopolysaccharide-Induced Acute Inflammation via Activation of GPR37 in Macrophages.

The G protein-coupled receptor 37 (GPR37) has been reported to be expressed in macrophages and the activation of GPR37 by its ligand/agonist, and it can regulate macrophage-associated functions and inflammatory responses. Since our previous work identified that osteocalcin (OCN) acts as an endogenous ligand for GPR37 and can elicit various intracellular signals by interacting with GPR37, we thus hypothesized that OCN may also play a functional role in macrophage through the activation of GPR37. To verify the hypothesis, we conducted a series of in vivo and in vitro studies in lipopolysaccharide (LPS)-challenged mice and primary cultured macrophages. Our results reveal that the OCN gene deletion (OCN−/−) and wild type (WT) mice showed comparable death rates and inflammatory cytokines productions in response to a lethal dose of LPS exposure. However, the detrimental effects caused by LPS were significantly ameliorated by exogenous OCN treatments in both WT and OCN−/− mice. Notably, the protective effects of OCN were absent in GPR37−/− mice. In coordination with the in vivo results, our in vitro studies further illustrated that OCN triggered intracellular responses via GPR37 in peritoneal macrophages by regulating the release of inflammatory factors and macrophage phagocytic function. Finally, we exhibited that the adoptive transfer of OCN-treated macrophages from WT mice significantly inhibits the release of pro-inflammatory cytokines in GPR37−/− mice exposed to LPS. Taken together, these findings suggest a protective role of OCN against LPS-caused acute inflammation, by the activation of GPR37 in macrophages, and provide a potential application of the activation of the OCN/GPR37 regulatory axis as a therapeutic strategy for inflammatory diseases.

Hedgehog Signalling Modulates Immune Response and Protects against Experimental Autoimmune Encephalomyelitis

The Hedgehog (Hh) pathway is essential for the embryonic development and homeostatic maintenance of many adult tissues and organs. It has also been associated with some functions of the innate and adaptive immune system. However, its involvement in the immune response has not been well determined. Here we study the role of Hh signalling in the modulation of the immune response by using the Ptch-1-LacZ+/− mouse model (hereinafter referred to as ptch+/−), in which the hemizygous inactivation of Patched-1, the Hh receptor gene, causes the constitutive activation of Hh response genes. The in vitro TCR stimulation of spleen and lymph node (LN) T cells showed increased levels of Th2 cytokines (IL-4 and IL-10) in ptch+/−cells compared to control cells from wild-type (wt) littermates, suggesting that the Th2 phenotype is favoured by Hh pathway activation. In addition, CD4+ cells secreted less IL-17, and the establishment of the Th1 phenotype was impaired in ptch+/− mice. Consistently, in response to an inflammatory challenge by the induction of experimental autoimmune encephalomyelitis (EAE), ptch+/− mice showed milder clinical scores and more minor spinal cord damage than wt mice. These results demonstrate a role for the Hh/ptch pathway in immune response modulation and highlight the usefulness of the ptch+/− mouse model for the study of T-cell-mediated diseases and for the search for new therapeutic strategies in inflammatory diseases.

A narrative review of the role of the Notch signaling pathway in rheumatoid arthritis.

Background and ObjectiveRheumatoid arthritis (RA) is a chronic autoimmune disease affected by genetics and the environment factors. Its early diagnosis and treatment are difficult, and the infection risk is serious. The treatment effects for most patients were not significant, which has become a difficult challenge to overcome. Cell signals play an important role in regulating basic cellular activities such as immunity. Notch signaling is a near secretory signal that can affects many processes of cell normal morphogenesis, including the differentiation of pluripotent progenitor cells, apoptosis, cell proliferation and the formation of cell boundary. In addition, the expression and activation of Notch signaling are increased in the synovial cells and vascular endothelial cells of RA patients. The purpose of this review was to elucidate the related mechanisms of Notch signaling in RA progression, as well as the potential therapeutic value of Notch signaling in a variety of autoimmune diseases.MethodsLiteratures about Notch signaling and RA were extensively reviewed to analyze and discuss.Key Content and FindingsThis article briefly reviews the role of Notch signaling in RA. It also summarizes the functional role of Notch signaling in the treatment of RA, with the goal to provide a new treatment option for RA patients.ConclusionsIn this review, the approach we discussed focuses on Notch signaling as a potential therapeutic target against RA, enriching therapeutic strategies for inflammatory diseases including RA.

Octyl gallate decrease lymphocyte activation and regulates neutrophil extracellular traps release.

Inflammation is a complex mechanism with an objective to destroy and eliminate the invading microorganisms. During acute inflammation, the neutrophils are the major cells involved in this process and, although they defend the organism, must die to not generate damage. The two major mechanisms that drive neutrophils to death are: apoptosis and a novel mechanism recently discovered denominated NETosis. This process is a "suicidal mechanism", in which the cells release "neutrophil extracellular traps" (NETs) during the inflammatory response. Octyl gallate (OG) is one of the gallic acid derivates, with several protective effects, such as antioxidant and anti-inflammatory in cancer models. Thus, this study aimed to investigate the action of OG on the proliferation of lymphocytes, neutrophils activation, and its effectiveness in an experimental sepsis model. Lymphocytes and neutrophils were obtained from healthy donors. Cell viability, apoptosis, NETs release and antioxidant capacity of OG were observed. In addition, survival was evaluated in an experimental model of sepsis in C57BL/6 mice. Our study demonstrated, for the first time, that the OG can act as an inhibitor of reactive oxygen species (ROS) release, NETs formation in primary human neutrophils and, modulates the lipopolysaccharide (LPS) effect in neutrophil apoptosis. The OG also inhibited peripheral blood mononuclear cells (PBMCs) proliferation in vitro. Despite the positive results, we did not observe an increase in the survival of septic animals. The pharmacological potential of OG, modulating activation of neutrophils and lymphocytes, suggests the use as an adjuvant therapeutic strategy in inflammatory diseases.

IL-6 enhances CD4 cell motility by sustaining mitochondrial Ca2+ through the noncanonical STAT3 pathway

Interleukin 6 (IL-6) is known to regulate the CD4 T cell function by inducing gene expression of a number of cytokines through activation of Stat3 transcription factor. Here, we reveal that IL-6 strengthens the mechanics of CD4 T cells. The presence of IL-6 during activation of mouse and human CD4 T cells enhances their motility (random walk and exploratory spread), resulting in an increase in travel distance and higher velocity. This is an intrinsic effect of IL-6 on CD4 T-cell fitness that involves an increase in mitochondrial Ca2+ Although Stat3 transcriptional activity is dispensable for this process, IL-6 uses mitochondrial Stat3 to enhance mitochondrial Ca2+-mediated motility of CD4 T cells. Thus, through a noncanonical pathway, IL-6 can improve competitive fitness of CD4 T cells by facilitating cell motility. These results could lead to alternative therapeutic strategies for inflammatory diseases in which IL-6 plays a pathogenic role.

Mdivi-1 alleviates atopic dermatitis through the inhibition of NLRP3 inflammasome.

Atopic dermatitis (AD) is a chronic inflammatory cutaneous disorder with few treatment options. Dynamin-related protein 1 (Drp1)-dependent mitochondrial fission contributes to the activation of NLRP3 inflammasome, and inhibiting Drp1has been become an attractive therapeutic strategy for inflammatory diseases. This study aimed to investigate the effects of Drp1 inhibitor mdivi-1 on experimental AD. We firstly detected the effects of mdivi-1 on primary human keratinocytes in an inflammatory cocktail-induced AD-related inflammation in vitro. Results showed that mdivi-1 inhibited NLRP3 inflammasome activation and pyroptosis which were evidenced by decreased expression of NLRP3, ASC, cleavage of caspase-1, GSDMD-NT, mature interleukin (IL)-1β and IL-18 in keratinocytes under AD-like inflammation. Next, mouse model of AD-like skin lesions was induced by epicutaneous application of 2,4-dinitrochlorobenzene (DNCB) and mdivi-1 (25mg/kg/day, days 5-33 during construction of AD model) was intraperitoneally injected into DNCB-induced mice. AD mice with mdivi-1 treatment exhibited ameliorated AD symptoms, lower serum IgE level, and reduced epidermal thickening, mast cells infiltration, and production of IL-4, IL-5 and IL-13 in the lesional tissues. Indeed, mdivi-1significantly inhibited NLRP3 inflammasome activation and pyroptotic injury occurred in DNCB-treated skin tissues. Mechanically, mdivi-1 regulated the expression of mitochondrial dynamic proteins and suppressed the activation of NF-κB signal pathway which is an upstream of NLRP3 inflammasome both in vitro and in vivo. This study demonstrated that mdivi-1 could protect against experimental AD through inhibiting the activation of NLRP3 inflammasome and subsequent inflammatory cytokine release, and mdivi-1might exert this function by inhibiting mitochondrial fission and subsequently blocking NF-κB pathway.

Design, synthesis and biological evaluation of 1H-indazole derivatives as novel ASK1 inhibitors.

Apoptosis signal-regulating kinase 1 (ASK1, MAP3K5), a member of the mitogen-activated protein kinase (MAPK) signaling pathway, is involved in cell survival, differentiation, stress response, and apoptosis. ASK1 kinase inhibition has emerged as a promising therapeutic strategy for inflammatory disease. A series of novel ASK1 inhibitors with 1H-indazole scaffold were designed, synthesized and evaluated for their ASK1 kinase activity and AP1-HEK293cell inhibitory effect. Systematic structure-activity relationship (SAR) efforts led to the discovery of promising compound 15, which showed excellent invitro ASK1 kinase activity and potent inhibitory effects on ASK1 in AP1-HEK293cells. In a tumor necrosis factor-α (TNF-α)-induced HT-29 intestinal epithelial cell model, compound 15 exhibited a significantly protective effect on cell viability comparable to that of GS-4997; moreover, compound 15 exhibited no obvious cytotoxicity against HT-29cells at concentrations up to 25μM. Mechanistic research demonstrated that compound 15 suppresses phosphorylation in the ASK1-p38/JNK signaling pathway in HT-29cells, and regulates the expression levels of apoptosis-related proteins. Altogether, these results show that compound 15 may serve as a potential candidate compound for the treatment of inflammatory bowel disease (IBD).

Targeting SHP2 as a therapeutic strategy for inflammatory diseases.

With the change of lifestyle and the acceleration of aging process, inflammatory diseases have increasingly become one of the most vital threats to global human health. SHP2 protein is a non-receptor tyrosine phosphatase encoded by PTPN11 gene, and it is widely expressed in various tissues and cells. Numerous studies have shown that SHP2 plays important roles in the regulation of inflammatory diseases, including cancer-related inflammation, neurodegenerative diseases and metabolic diseases. In this paper, the roles of SHP2 in inflammatory diseases of various physiological systems were reviewed. At the same time, the latest SHP2 inhibitors were summarized, which will hold a promise for the therapeutic potential in future.