Investigating immunoregulatory effects of myeloid cell autophagy in acute and chronic inflammation

Md Abul Hasnat, Ian Ian Cheang, Wendy Dankers, Jacinta P.W. Lee, Lynda M. Truong, Mehnaz Pervin, Sarah A. Jones, Eric F. Morand, Joshua D. Ooi, James Harris

Research output: Contribution to journalArticleResearchpeer-review

1 Citation (Scopus)

Abstract

Studies have highlighted a critical role for autophagy in the regulation of multiple cytokines. Autophagy inhibits the release of interleukin (IL)-1 family cytokines, including IL-1α, IL-1β and IL-18, by myeloid cells. This, in turn, impacts the release of other cytokines by myeloid cells, as well as other cells of the immune system, including IL-22, IL-23, IL-17 and interferon-γ. Here, we assessed the impact of genetic depletion of the autophagy gene Atg7 in myeloid cells on acute and chronic inflammation. In a model of acute lipopolysaccharide-induced endotoxemia, loss of autophagy in myeloid cells resulted in increased release of proinflammatory cytokines, both locally and systemically. By contrast, loss of Atg7 in myeloid cells in the Lyn−/− model of lupus-like autoimmunity resulted in reduced systemic release of IL-6 and IL-10, with no effects on other cytokines observed. In addition, Lyn−/− mice with autophagy-deficient myeloid cells showed reduced expression of autoantibodies relevant to systemic lupus erythematosus, including anti-histone and anti-Smith protein. In vitro, loss of autophagy, through pharmacological inhibition or small interfering RNA against Becn1, inhibited IL-10 release by human and mouse myeloid cells. This effect was evident at the level of Il10 messenger RNA expression. Our data highlight potentially important differences in the role of myeloid cell autophagy in acute and chronic inflammation and demonstrate a direct role for autophagy in the production and release of IL-10 by macrophages.

Original languageEnglish
Pages (from-to)605-623
Number of pages19
JournalImmunology and Cell Biology
Volume100
DOIs
Publication statusPublished - Sept 2022

Keywords

  • Atg7
  • autoimmunity
  • IL-10
  • IL-6
  • Lyn
  • systemic lupus erythematosus

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