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Essential role of M1 macrophages in blocking cytokine storm and pathology associated with murine HSV-1 infection.

ABSTRACT: Ocular HSV-1 infection is a major cause of eye disease and innate and adaptive immunity both play a role in protection and pathology associated with ocular infection. Previously we have shown that M1-type macrophages are the major and earliest infiltrates into the cornea of infected mice. We also showed that HSV-1 infectivity in the presence and absence of M2-macrophages was similar to wild-type (WT) control mice. However, it is not clear whether the absence of M1 macrophages plays a role in protection and disease in HSV-1 infected mice. To explore the role of M1 macrophages in HSV-1 infection, we used mice lacking M1 activation (M1-/- mice). Our results showed that macrophages from M1-/- mice were more susceptible to HSV-1 infection in vitro than were macrophages from WT mice. M1-/- mice were highly susceptible to ocular infection with virulent HSV-1 strain McKrae, while WT mice were refractory to infection. In addition, M1-/- mice had higher virus titers in the eyes than did WT mice. Adoptive transfer of M1 macrophages from WT mice to M1-/- mice reduced death and rescued virus replication in the eyes of infected mice. Infection of M1-/- mice with avirulent HSV-1 strain KOS also increased ocular virus replication and eye disease but did not affect latency-reactivation seen in WT control mice. Severity of virus replication and eye disease correlated with significantly higher inflammatory responses leading to a cytokine storm in the eyes of M1-/- infected mice that was not seen in WT mice. Thus, for the first time, our study illustrates the importance of M1 macrophages specifically in primary HSV-1 infection, eye disease, and survival but not in latency-reactivation.

SUBMITTER: Jaggi U

PROVIDER: S-EPMC8550391 | biostudies-literature | 2021 Oct

REPOSITORIES: biostudies-literature

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Essential role of M1 macrophages in blocking cytokine storm and pathology associated with murine HSV-1 infection.

Jaggi Ujjaldeep U Matundan Harry H HH Yu Jack J Hirose Satoshi S Mueller Mathias M Wormley Floyd L FL Ghiasi Homayon H

PLoS pathogens 20211015 10

Ocular HSV-1 infection is a major cause of eye disease and innate and adaptive immunity both play a role in protection and pathology associated with ocular infection. Previously we have shown that M1-type macrophages are the major and earliest infiltrates into the cornea of infected mice. We also showed that HSV-1 infectivity in the presence and absence of M2-macrophages was similar to wild-type (WT) control mice. However, it is not clear whether the absence of M1 macrophages plays a role in pro ...[more]

PMID: 34653236

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Project description:BackgroundAlpha-momorcharin (α-MMC) is a natural medicine derived from bitter melon and has been found to exert immunomodulatory effects. Our previous study indicated that α-MMC can regulate cytokine release from monocytes, but it remains unknown about its regulatory effect on different types of cytokines, such as inflammatory cytokines or anti-inflammatory cytokines.MethodsLPS-induced M1-type macrophages model and IL-4-induced M2-type macrophages model were established, and the expression of proinflammatory cytokines and anti-inflammatory cytokines were assessed by ELISA after α-MMC was administered. Then, a LPS-induced acute pneumonia mouse model was established, the proinflammatory cytokines levels and inflammatory lesions in lung tissues were examined by ELISA or H&E staining. Furthermore, omics screening analysis and Western blotting verification were performed on TLR4 and JAK1-STAT6 signalling pathway-related proteins to elucidate the regulatory mechanism of α-MMC in those M1 macrophages and M2 macrophages.ResultsAt a noncytotoxic dose of 0.3 μg/mL, α-MMC significantly inhibited the LPS-induced expression of inflammatory cytokines, such as TNF-α, IL-1β, IL-6, IL-8, MIP-1α and MCP-1, by M1 macrophages in a time-dependent manner, but α-MMC did not inhibit the IL-4-induced synthesis of anti-inflammatory cytokines, such as IL-10, IL-1RA, EGF, VEGF, TGF-β and CCL22, by M2 macrophages. Moreover, α-MMC also inhibited inflammatory cytokine expression in an LPS-induced acute pneumonia mouse model and alleviated inflammation in lung tissues. Furthermore, omics screening and Western blotting analysis confirmed that α-MMC inhibited TAK1/p-TAK1 and subsequently blocked the downstream MAPK and NF-κB pathways, thus inhibiting the LPS-induced inflammatory cytokine expression.ConclusionOur results reveal that α-MMC inhibits proinflammatory cytokine expression by M1 macrophages but not anti-inflammatory cytokine expression by M2 macrophages. The efficacy of α-MMC in selectively inhibiting proinflammatory cytokine expression renders it particularly suitable for the treatment of severe inflammation and autoimmune diseases characterized by cytokine storms.

Project description:ObjectivesOur understanding of the immunopathogenesis of coronavirus disease 2019 is evolving; however, a "cytokine storm" has been implicated. Ongoing clinical trials are evaluating the value of anticytokine therapies to treat patients with coronavirus disease 2019. This review summarizes the existing literature evaluating the efficacy and safety of anticytokine therapy to tackle the dysregulated immune response to infectious pathogens, discusses potential reasons for failure, applicability to coronavirus disease 2019, and future direction.Data sourcesMedline, PubMed, ClinicalTrials.gov, and media reports.Study selectionThe studies were included by author consensus.Data extractionData were selected for inclusion after reviewing each study by author consensus.Data synthesis"Cytokine storm" is a nonspecific term, encompassing systemic inflammatory response to infectious pathogens, autoimmune conditions, cancers, trauma, and various chemotherapies. Like bacterial sepsis, viral pathogens may fuel immunopathogenesis by inducing a dysregulated autoamplifying cytokine cascade, ultimately leading to organ injury. This narrative review discusses what we know of the immune milieu of coronavirus disease 2019 versus noncoronavirus disease 2019 sepsis and/or acute respiratory distress syndrome, summarizes the existing literature on cytokine inhibitors in patients with sepsis and/or acute respiratory distress syndrome, and discusses possible reasons for recurrent failure. In doing so, it aims to assist decisions regarding the use of anticytokine therapy in patients with coronavirus disease 2019, as many regions of the world confront the second wave of the pandemic.ConclusionsAs ongoing clinical trials determine the efficacy and safety of anticytokine therapy in patients with coronavirus disease 2019, clinicians should uphold caution when incorporating it into treatment protocols, while maintaining focus on established evidence-based practices and the mantra of "less is more."

Dataset Information

Essential role of M1 macrophages in blocking cytokine storm and pathology associated with murine HSV-1 infection.

Publications

Essential role of M1 macrophages in blocking cytokine storm and pathology associated with murine HSV-1 infection.

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