TY - JOUR
T1 - Investigating immunoregulatory effects of myeloid cell autophagy in acute and chronic inflammation
AU - Hasnat, Md Abul
AU - Cheang, IanIan
AU - Dankers, Wendy
AU - Lee, Jacinta P. W.
AU - Truong, Lynda M.
AU - Pervin, Mehnaz
AU - Jones, Sarah A.
AU - Morand, Eric F.
AU - Ooi, Joshua D.
AU - Harris, James
N1 - Funding Information: The authors acknowledge the hard work and invaluable assistance of the staff at the Monash Medical Centre Animal Facility (MMCAF). This work was supported by a Project Grant (1068040) from the Australian National Health and Medical Research Foundation (NHMRC) and by donations from the Lions Rheumatism and Arthritis Medical Research Foundation Australia. Open access publishing facilitated by Monash University, as part of the Wiley ‐ Monash University agreement via the Council of Australian University Librarians. Publisher Copyright: © 2022 The Authors. Immunology & Cell Biology published by John Wiley & Sons Australia, Ltd on behalf of Australian and New Zealand Society for Immunology, Inc.
PY - 2022/9
Y1 - 2022/9
N2 - 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.
AB - 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.
KW - Atg7
KW - IL-10
KW - IL-6
KW - Lyn
KW - autoimmunity
KW - systemic lupus erythematosus
UR - http://www.scopus.com/inward/record.url?scp=85132195304&partnerID=8YFLogxK
U2 - https://doi.org/10.1111/imcb.12562
DO - https://doi.org/10.1111/imcb.12562
M3 - Article
C2 - 35652357
SN - 0818-9641
VL - 100
SP - 605
EP - 623
JO - Immunology and Cell Biology
JF - Immunology and Cell Biology
IS - 8
ER -