Infiltrating macrophages replace Kupffer cells and play diverse roles in severe alcohol-associated hepatitis

Cell Type–Dependent Pro- and Anti-Inflammatory Role of Signal Transducer and Activator of Transcription 3 in Alcoholic Liver Injury

Measuring the progression of trauma induced osteoarthritis in CCN2 deficient mice

C-reactive protein (CRP) has been shown to be a potential candidate target in the immunotherapy of severe influenza A infection. However, it is unclear on the pathogenesis associated with CRP in influenza infections. Here, we used influenza A H1N1 CA04 to infect human CRP transgenic mice (KI), CRP knockout mice (KO), and wild-type mice (WT), respectively, and compared the viral pathogenicity and associated immune response in those mice. The results showed that CA04 infection resulted in 100%, 80%, and 60% death in KO, KI, and WT mice, respectively. Compared to WT mice, CA04 infection resulted in higher TCID50 in lungs on day 3 after infection but lowered HI antibody titers in sera of survivors on day 21 after infection in KI mice. ELISA assay showed that IFN-γ concentration was significantly increased in sera of WT, KI, or KO mice on day 7 after infection, and IL-17 was remarkably increased in sera of WT mice but decreased in sera of KI mice while no significant change in sera of KO mice on day 3 or 7 after infection. Quantitative RT-PCR showed that the relative expression levels of immune checkpoint CTLA-4, LAIR-1, GITR, BTLA, TIM-3, or PD-1 mRNA in the lung presented decreased levels on day 3 or 7 after infection in KI or KO mice. The correlation analysis showed that mRNA expression levels of the 6 molecules positively correlated with viral TICD50 in WT mice but negatively correlated with viral TCID50 in KI or KO mice. However, only LAIR-1 presented a significant correlation in each lung tissue of WT, KI, or KO mice with CA07 infection statistically. IHC results showed that LAIR-1 positive cells could be found in WT, KO, or KI mice lung tissues with CA04 infection, and the positive cells were mainly distributed in an inflammatory dense area. Our results suggested that deficiency of CRP or human CRP transgenic treatment aggravates influenza A virus infection in mice. CRP is a double sword in immune regulation of influenza infection in which IL-17 and immune checkpoint may be involved.

The cuprizone (CPZ) model of multiple sclerosis (MS) was used to identify microRNAs (miRNAs) related to in vivo de- and remyelination. We further investigated the role of miR-146a in miR-146a-deficient (KO) mice: this miRNA is differentially expressed in MS lesions and promotes differentiation of oligodendrocyte precursor cells (OPCs) during remyelination, but its role has not been examined during demyelination. MicroRNAs were examined by Agilent Mouse miRNA Microarray in the corpus callosum during CPZ-induced demyelination and remyelination. Demyelination, axonal loss, changes in number of oligodendrocytes, OPCs, and macrophages/microglia was compared by histology/immunohistochemistry between KO and WT mice. Differential expression of target genes and proteins of miR-146a was analyzed in the transcriptome (4 × 44K Agilent Whole Mouse Genome Microarray) and proteome (liquid chromatography tandem mass spectrometry) of CPZ-induced de- and remyelination in WT mice. Levels of proinflammatory molecules in the corpus callosum were compared in WT versus KO mice by Meso Scale Discovery multiplex protein analysis. miR-146a was increasingly upregulated during CPZ-induced de- and remyelination. The absence of miR-146a in KO mice protected against demyelination, axonal loss, body weight loss, and atrophy of thymus and spleen. The number of CNP+ oligodendrocytes was increased during demyelination in the miR-146a KO mice, while there was a trend of increased number of NG2+ OPCs in the WT mice. miR-146a target genes, SNAP25 and SMAD4, were downregulated in the proteome of demyelinating corpus callosum in WT mice. Higher levels of SNAP25 were measured by ELISA in the corpus callosum of miR-146a KO mice, but there was no difference between KO and WT mice during demyelination. Multiplex protein analysis of the corpus callosum lysate revealed upregulated TNF-RI, TNF-RII, and CCL2 in the WT mice in contrast to KO mice. The number of Mac3+ and Iba1+ macrophages/microglia was reduced in the demyelinating corpus callosum of the KO mice. During demyelination, absence of miR-146a reduced inflammatory responses, demyelination, axonal loss, the number of infiltrating macrophages, and increased the number of myelinating oligodendrocytes. The number of OPCs was slightly higher in the WT mice during remyelination, indicating a complex role of miR-146a during in vivo de- and remyelination.

HomeCirculationVol. 116, No. suppl_16Abstract 1365: Role of Kv1.5 in Atrial Fibrillation: KCNA5-Deficient Mice Do Not Have Enhanced Arrhythmia Susceptibility Free AccessMeeting ReportAboutSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessMeeting ReportBasic ScienceElectrophysiologyAbstract 1365: Role of Kv1.5 in Atrial Fibrillation: KCNA5-Deficient Mice Do Not Have Enhanced Arrhythmia Susceptibility Danshi Li, Huabin Sun, Jialong Zhu, Margeret A Liu, Stanley Nattel and Paul C Levesque Danshi LiDanshi Li Search for more papers by this author , Huabin SunHuabin Sun Search for more papers by this author , Jialong ZhuJialong Zhu Search for more papers by this author , Margeret A LiuMargeret A Liu Search for more papers by this author , Stanley NattelStanley Nattel Search for more papers by this author and Paul C LevesquePaul C Levesque Search for more papers by this author Originally published16 Oct 2007https://doi.org/10.1161/circ.116.suppl_16.II_280-aCirculation. 2007;116:II_280AbstractBackground: A loss-of-function mutation in KCNA5, the gene that encodes the voltage-gated K+ channel Kv1.5 (IKur) in human atria, has been reported in an AF case ( Hum Mol Genet.2006; 15:2185Google Scholar). Kv1.5 encodes K+ currents in mouse atria and ventricles, and inhibition of Kv1.5 with 4-AP delays mouse cardiac repolarization. We examined the role of Kv1.5 in atrial arrhythmogenesis using KCNA5 KO mice.Methods: Electrophysiologic features were studied with standard EP protocols in anesthetized, adult WT (n=18) and Kv1.5 −/− KO (n=23) mice using a right atrial 2F octapolar catheter. AF induction was performed in the absence and presence of isoproterenol (iso 5 μg, IP) with triple extra stimulation and burst pacing (20 –50 Hz). AF was considered inducible if ≥1 bursts or triple extra stimulation evoked an AF episode ≥0.1 sec. Action potentials (APs) were recorded from isolated WT (n=5) and KO (n=8) left atrium at 1 Hz in the absence and presence of 1μM iso using standard microelectrodes.Results: Taqman did not detect any Kv1.5 mRNA in KO heart, and there were no differences in Kv1.4, Kv2.1 and Kv4.2 mRNAs between WT and KO mice. Mean±SEM atrial ERP, HR and SNRT were not significantly different between KO and WT mice. No spontaneous atrial or ventricular arrhythmias were observed in KO or WT mice. Burst pacing induced AF in 2 of 10 KO and 1 of 8 WT mice without iso, and in 4 of 10 KO and 5 of 8 WT mice with iso, with no statistical difference among groups. Iso increased AF duration (AFD) in both WT and KO, but AFD under iso was longer in WT versus KO mice. There was no difference in AV node function (PR, AVN-ERP and Wenckebach CL) between KO and WT mice. APD90 was prolonged in KO (45±5 vs 39±2, P=0.06) but other AP indices were unchanged. Iso induced more EAD, DAD and atrial tachycardia-like activity in WT (5/5) than in KO (3/8, P<0.05).Conclusions: This study, the first to examine the role of Kv1.5 in AF using a KO approach, indicates that loss of Kv1.5 does not enhance AF susceptibility and may in fact reduce it. Previous Back to top Next FiguresReferencesRelatedDetails October 16, 2007Vol 116, Issue suppl_16 Advertisement Article InformationMetrics https://doi.org/10.1161/circ.116.suppl_16.II_280-a Originally publishedOctober 16, 2007 Advertisement

The V-ATPase, or proton pump, generates electrochemical gradients across membranes driving cell biological processes. The kidney-specific V-ATPase is expressed in intercalated cells (ICs), which regulate acid-base homeostasis by adjusting plasma membrane V-ATPase via regulated traffcking. In the kidney, A-ICs transport protons into the tubule lumen while B-ICs move protons into the peritubular space and, ultimately, the blood. The V-ATPase is distributed between intracellular vesicles and the apical plasma membrane in A-ICs, whereas B-ICs express V-ATPase not only in intracellular vesicles, but also basolaterally. In general, V-ATPase dysfunction in ICs leads to distal renal tubular acidosis (dRTA) implying a functional dominance of A-IC in acid/base physiology. B-ICs have, however, been implicated in blood pressure regulation due to their role in chloride reabsorption and, indirectly, Na transport. We recently identified a new class of V-ATPase interacting proteins defined by their TLDc domain (Ncoa7, Oxr1, Tbc1d24, Tldc1, Tldc2), all of which interact with the IC-specific B1 subunit of the V-ATPase. Of importance, Ncoa7 knockout mice had decreased V-ATPase expression in ICs and developed dRTA, which led us to hypothesize that TLDc proteins regulate the kidney V-ATPase. While Ncoa7 is specifically expressed in A-ICs, Tldc2 is one of the most differentially expressed proteins in B-ICs, prompting us to ask whether Tldc2 deletion affected V-ATPase function in these cells. Using global Tldc2 knockout mice (KO), we found that urine pH is significantly more acidic in KO mice than in WT mice in both males and females (pH 5.8 in male KOs versus pH 6.4 in male WTs and pH 5.8 in female KOs versus pH 6.2 in female WTs). After an acid challenge with NH4Cl, the urine pH of WT mice was significantly decreased, but urine pH was unchanged in KO mice, since it was already low under baseline conditions (pH 5.8 for male and female WT and KO mice). After base challenging mice with NaHCO3−, urine pH was greatly increased in WT mice (pH 7.8 in male WTs and pH 7.5 in female WTs), while urine pH increased to a lesser, but still significant amount, in KO mice (pH 6.3 in male KOs and 7.2 in female KOs). Interestingly, after the bicarbonate challenge urine pH was significantly lower in KO males versus WT males (pH 6.3 in male KOs versus pH 7.8 in male WTs). In females, urine pH was also lower in KO mice versus WT mice after the base challenge but did not reach statistical significance due to high variability between mice (pH 7.2 in female KOs versus pH 7.5 in female WTs). There was no significant difference in blood pH between Tldc2 KO and Tldc2 WT mice of either sex, with or without treatment, suggesting possible respiratory compensation. The inability of KO mice to alkalinize their urine points to a defect in bicarbonate-secreting B-ICs, in which Tldc2 is specifically expressed. To examine this, localization of the B1 subunit was visualized in B-ICs by immunofluorescence, and membrane accumulation was quantified by line intensity scanning using FIJI. Our preliminary results show that basolateral membrane accumulation of B1 was reduced in KO mice relative to WT mice. In summary, our data suggest that loss of Tldc2 negatively affects B-IC function most likely by impairing basolateral accumulation of the V-ATPase. We conclude that Tldc2 is part of a regulatory mechanism that participates in the accumulation of the V-ATPase holoenzyme at the basolateral surface of B-ICs. Whether this is due to changes in assembly or traffcking of the holoenzyme remains to be determined. NIH/NIDDK R01DK121848. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

To compare inflammatory cytokine and defensin expression in response to experimental dry eye (EDE) in interleukin-1 receptor-1 (IL-1R1)-deficient (KO) mice with age-matched wild-type mice (WT). EDE was induced by subcutaneous scopolamine injection, exposure to low humidity, and an air draft for 5 days in 4- to 6-week-old KO and WT mice. Expression of cytokines IL-1 alpha, IL-1 beta, tumor necrosis factor (TNF)-alpha, IL-6, and mouse beta-defensins (mBD)-1, mBD-2, and mBD-3 was evaluated by real-time polymerase chain reaction in scraped corneal epithelial cells and whole conjunctival tissues. A multiplex bead assay was performed to quantitate IL-1 alpha, IL-2, IL-4, IL-10, interferon (IFN)-gamma, and TNF-alpha levels in tear fluid, and an enzyme immunoassay was used to quantitate IL-1 beta levels in tear fluid. EDE significantly increased RNA transcripts for IL-1 alpha and beta in the conjunctiva and for TNF-alpha in the corneal epithelium of WT mice. Levels of IL-1 alpha, IL-1 beta, and IL-6 were significantly lower in the corneal epithelium and conjunctiva, and TNF-alpha was significantly lower in the cornea of KO mice after 5 days of EDE than WT mice. Tear fluid IL-1 alpha concentration increased above baseline on days 2-4 of EDE in WT and KO mice. A similar pattern was observed for tear TNF-alpha. Tear IL-1 beta increased throughout the 5 days of EDE in WT and KO mice. IFN-gamma, IL-2, IL-4, and IL-10 were undetectable in tear fluid of either strain before or after EDE. Corneal mBD-1 mRNA expression was unchanged and conjunctival mBD-1 transcripts decreased in WT and increased in KO mice with EDE. Untreated WT corneas, but not those of KO mice, expressed mBD-2 transcripts, whereas in the conjunctiva, mBD-2 increased in WT and decreased in KO mice with EDE. Corneal mBD-3 mRNA expression was undetected in WT mice, but increased after EDE in KO mice. Conjunctival mBD-3 transcripts were only detected in WT with EDE. These findings indicate that IL-1 signaling is responsible in part for the increased expression of inflammatory cytokines and the changes in mBDs by the ocular surface tissues in response to desiccating stress. These results show the important regulatory aspects of IL-1 on ocular surface epithelial inflammation.

Among the many factors related to bone marrow cell mobilization, local inflammation induced by cytokines may drive bone marrow cells to the vascular wall, resulting in a thickened neointima. However, the relationship between inflammatory reactions and bone marrow cell invasion has not yet been fully clarified. We inserted a large wire into the femoral artery in male balb/c(WT), interleukin (IL)-6-knockout (KO) and bone marrow-transplanted (BMT) mice that had received bone marrow cells from KO mice. Immunohistochemistry was performed to evaluate the degree of intimal hyperplasia and inflammation following vascular injury. Three days after the vascular injury, the number of CD34/Sca-1-positive cells in the blood was higher in the KO mice. The numbers of apoptotic cells in the neointima was lower in the KO and BMT mice at two hours after injury. The morphometric analysis performed at one and four weeks after injury showed that the intima/media ratio was significantly lower in the KO and BMT mice, while CD34-positive cells were much more frequent in the WT mice. Furthermore, re-endothelialization appeared earlier in the KO and BMT mice than in the WT mice. No differences in the levels of vascular endothelial growth factor or hepatocyte growth factor were observed in the mice sera between the WT, KO and BMT mice after injury. The in vitro culture of bone marrow cells showed more differentiated smooth muscle-like cells in the WT mice than in the KO mice. IL-6 is involved in neointimal formation following vascular injury, possibly acting through inflammatory effects inducing the production of bone marrow cells.

We have shown that the acute hypertensive response to psychosocial stress is AngII-dependent, and also that it is attenuated in IL-6 KO mice. In addition, we have shown that chronic AngII infusion amplified the difference between KO and Wt mice. The goal of this study was to determine whether blocking AngII production would eliminate the difference in the acute hypertensive response. MAP and heart rate was continuously recorded via telemetry for 90 min. during cage-switch stress testing. Area under the curve (AUC) for MAP averaged 1759±62 and 1136±423 mmHg∗min in Wt (n=3) and KO (n=5) mice, respectively, confirming our previous report that the response was attenuated in KO mice. Captopril decreased AUC in the Wt mice (n=4) to an average of 1264±155 mmHg∗min, also confirming our report that the pressor response to acute stress is AngII dependent. In KO mice, AUC for the captopril treated vs. vehicle treated (n=5) mice was greater, averaging 1712±571 mmHg∗min. On the other hand, we measured an increase in the heart rate AUC response to stress in captopril treated KO mice vs. vehicle, averaging 9662±1441 vs. 6261±1063 bpm∗min, resp., which did not occur in the Wt mice. Although heart rate increased in all groups during stress, this difference in the response in KO mice treated with captopril vs. vehicle treated suggests that an interaction between AngII and IL-6 on the control of heart rate may play a role in the acute hypertensive response to psychosocial stress.

Macrophage heterogeneity in liver injury and fibrosis

Chronic alcohol consumption impairs gut barrier function and perturbs the gut microbiome. Although shifts in bacterial communities in patients with alcohol-associated liver disease (ALD) have been characterized, less is known about the interactions between host metabolism and circulating microbe-derived metabolites during the progression of ALD. A large panel of gut microbiome-derived metabolites of aromatic amino acids was quantified by stable isotope dilution liquid chromatography with online tandem mass spectrometry in plasma from healthy controls (n = 29), heavy drinkers (n = 10), patients with moderate (n = 16) or severe alcohol-associated hepatitis (n = 40), and alcohol-associated cirrhosis (n = 10). The tryptophan metabolites, serotonin and indole-3-propionic acid, and tyrosine metabolites, p-cresol sulfate, and p-cresol glucuronide, were decreased in patients with ALD. Patients with severe alcohol-associated hepatitis and alcohol-associated cirrhosis had the largest decrease in concentrations of tryptophan and tyrosine-derived metabolites compared to healthy control. Western blot analysis and interrogation of bulk RNA sequencing data from patients with various liver pathologies revealed perturbations in hepatic expression of phase II metabolism enzymes involved in sulfonation and glucuronidation in patients with severe forms of ALD. We identified several metabolites decreased in ALD and disruptions of hepatic phase II metabolism. These results indicate that patients with more advanced stages of ALD, including severe alcohol-associated hepatitis and alcohol-associated cirrhosis, had complex perturbations in metabolite concentrations that likely reflect both changes in the composition of the gut microbiome community and the ability of the host to enzymatically modify the gut-derived metabolites.

BackgroundAlcohol consumption and obesity are known synergistic risk factors of steatohepatitis. Combination of high fat diet (HFD) and acute alcohol synergistically induced acute liver inflammation via enhanced hepatic neutrophil infiltration. CRAMP (Cathelicidin‐related antimicrobial peptide), the murine ortholog of LL‐37, which is the only known member of human cathelicidin antimicrobial peptide family, possess both anti‐ and pro‐inflammatory activity. Our previous studies showed that CRMAP deficiency exacerbated binge‐on‐chronic alcohol‐induced liver injury. Here we aimed to investigate the role of CRAMP in alcohol‐induced liver injury in HFD fed mice, and to explore the underlying mechanism.MethodsCRAMP KO mice (Camp−/−) and wild type (WT) mice were fed control diet (CD) or HFD for 10 weeks, a bolus of alcohol was gavaged 9 hours before sample harvesting.ResultsTen‐week HFD + acute alcohol markedly induced liver steatosis and injury in WT mice, reflected by significantly increased liver macrosteatosis and serum levels of AST and ALT. Immunofluorescent assay showed a significantly stronger staining of Ly6G in the livers of mice treated with HFD + acute alcohol compared to CD feeding + acute alcohol, indicating an increased neutrophil infiltration. Interestingly, HFD+acute alcohol treatment significantly increased hepatic protein levels of CRAMP, which co‐localized with Ly6G‐positive neutrophils. In addition, hepatic mRNA expression of chemokines, Mcp‐1 and Cxcl‐2, was markedly increased. Depletion of Camp gene (Camp−/−) markedly reduced HFD + acute alcohol‐induced liver steatosis, injury and neutrophil infiltration, along with reduced expression of Mcp‐1. Importantly, feeding Camp−/− mice with HFD + acute alcohol significantly reduced the mRNA expression level of Cxcr‐2, a known CRAMP receptor. In vitro study showed that synthetic CRAMP peptide increased neutrophil migration, which was dependent on Cxcr‐2 expression upon treatment by fatty acid and ethanol. In addition, significantly decreased mRNA levels of hepatic Tgf‐β and Col‐1a1 were found in Camp−/− mice compared to WT mice, suggesting that CRAMP may play a role in hepatic stellate cells activation.ConclusionsHFD + acute alcohol treatment synergistically induces liver injury through systemic upregulation of chemoattractant CRAMP and subsequent enhancement of hepatic neutrophil infiltration. CRAMP deficiency protects against acute alcohol‐induced steatohepatitis in the HFD primed mice.Support or Funding InformationSupported by grants from NIHSchematic hypothesis of CRAMP‐mediated neutrophils infiltration in HFD and alcohol‐induced liver injury in miceFigure 1

G020 Properties of pulmonary artery smooth muscle from task-1 knockout mice

The dense network of sympathetic efferent and sensory afferent nerves innervating the kidney is well recognized, however the elements and the functional importance of neurotrophin signaling in renal tissues are much less known. Peripherally innervated tissues are known to produce and release nerve growth factor (NGF) which belongs to the neurotrophin family of neuronal signaling proteins and is essential for the growth and survival of peripheral sensory and sympathetic nerves. This study aimed to characterize the expression and role of NGF in the kidney. We hypothesized that NGF is produced by multiple renal tubular and vascular cell types and helps to maintain hemodynamic and tubular transport functions. Local NGF expression was studied using histological sections of kidneys harvested from NGF-GFP reporter mice. To address the functional importance of NGF signaling, a new mouse model was generated by crossing Ren1d-Cre and NGF-floxed mice and Cre/lox-mediated knockout of NGF from cells of the renin lineage co-labeled with the multicolor reporter Confetti (Ren1d-Confetti-NGF KO). WT and NGF KO mice were placed in metabolic cages for urine collections and analysis, and systolic blood pressure (SBP) was measured with tail-cuff pletysmography. Intercalated cells of the collecting duct (CD) showed by far the highest NGF expression among all renal cell types based on the reporter signal in NGF-GFP mice, in addition to select cells in the renal interstitium including juxtaglomerular (JG) renin cells. Since both CD cells and JG cells are part of the renin lineage, the applied genetic strategy using Ren1d-Confetti-NGF KO mice was ideal, and showed diminished NGF expression compared to WT. Urine excretion rate and albuminuria were 3-fold increased in Ren1d-Confetti-NGF KO vs. WT mice, while there was no difference in SBP between WT and KO groups. Immunohistochemistry showed aberrant CD structure with multiple small, undifferentiated cells with apparently lost polarity and reduced AQP2 labeling in CD principal cells in Ren1d-Confetti-NGF KO mice compared to WT. In addition, the characteristic strong apical membrane AQP2 (in principal cells) and H+-ATPase (in intercalated cells) labeling in WT mice was diminished in Ren1d-Confetti-NGF KO mice. JG renin cell number per nephron was significantly reduced in Ren1d-Confetti-NGF KO (2.5±1.0) vs. WT mice (6.2±1.5, n=4 mice each). In summary, our results suggest high level of NGF expression in the adult kidney that plays important physiological functional roles in maintaining collecting duct water and electrolyte reabsorption and acid secretion, and intrarenal renin production. Deficient intrarenal NGF production may cause kidney disease, suggesting the importance of altered renal neurotrophin signaling in pathology development. DK064234, DK123564, DK135290. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Alterations in the energy homeostasis contribute to sepsis-mediated multiple organ failure. The liver plays a central role in metabolism and participates to the innate immune and inflammatory responses of sepsis. Several clinical and experimental studies have suggested that females are less susceptible to the adverse outcome of sepsis. However, underlying mechanisms of organ damage in sepsis remain largely undefined. AMP-activated protein kinase (AMPK) is an important regulator of mitochondrial quality control. The AMPK catalytic α1 isoform is abundantly expressed in the liver. Here, we determined the role of hepatocyte AMPKα1 in sepsis by using hepatocyte-specific AMPKα1 knockout mice (H-AMPKα1 KO) generated with Cre-recombinase expression under the control of the albumin promoter. Using a clinically relevant model of polymicrobial sepsis by cecal ligation and puncture (CLP), we observed that male H-AMPKα1 KO mice had higher plasma levels of tumor necrosis factor-α and interleukin-6 and exhibited a more severe liver and lung injury than male H-AMPKα1 WT mice, as evaluated by histology and neutrophil infiltration at 18 h after CLP. Plasma levels of interleukin-10 and the keratinocyte-derived chemokine were similarly elevated in both KO and WT male mice. At transmission electron microscopy analysis, male H-AMPKα1 KO mice exhibited higher liver mitochondrial damage, which was associated with a significant decrease in liver ATP levels when compared to WT mice at 18 h after sepsis. Mortality rate was significantly higher in the male H-AMPKα1 KO group (91%) when compared to WT mice (60%) at 7 days after CLP. Female H-AMPKα1 WT mice exhibited a similar degree of histological liver and lung injury, but significantly milder liver mitochondrial damage and higher autophagy when compared to male WT mice after CLP. Interestingly, H-AMPKα1 KO female mice had lower organ neutrophil infiltration, lower liver mitochondrial damage and lower levels of cytokines than WT female mice. There was no significant difference in survival rate between WT and KO mice in the female group. In conclusion, our study demonstrates that AMPKα1 is a crucial hepatoprotective enzyme during sepsis. Furthermore, our results suggest that AMPK-dependent liver metabolic functions may influence the susceptibility to multiple organ injury in a sex-dependent manner.