IL-36γ is a crucial proximal component of protective type-1-mediated lung mucosal immunity in Gram-positive and -negative bacterial pneumonia.
Interleukin-36γ (IL-36γ) is a member of novel IL-1-like proinflammatory cytokine family that are highly expressed in epithelial tissues and several myeloid-derived cell types. Little is known about the role of the IL-36 family in mucosal immunity, including lung anti-bacterial responses. We used murine models of IL-36γ deficiency to assess the contribution of IL-36γ in the lung during experimental pneumonia. Induction of IL-36γ was observed in the lung in response to Streptococcus pneumoniae (Sp) infection, and mature IL-36γ protein was secreted primarily in microparticles. IL-36γ-deficient mice challenged with Sp demonstrated increased mortality, decreased lung bacterial clearance and increased bacterial dissemination, in association with reduced local expression of type-1 cytokines, and impaired lung macrophage M1 polarization. IL-36γ directly stimulated type-1 cytokine induction from dendritic cells in vitro in a MyD88-dependent manner. Similar protective effects of IL-36γ were observed in a Gram-negative pneumonia model (Klebsiella pneumoniae). Intrapulmonary delivery of IL-36γ-containing microparticles reconstituted immunity in IL-36γ-/-mice. Enhanced expression of IL-36γ was also observed in plasma and bronchoalveolar lavage fluid of patients with acute respiratory distress syndrome because of pneumonia. These studies indicate that IL-36γ assumes a vital proximal role in the lung innate mucosal immunity during bacterial pneumonia by driving protective type-1 responses and classical macrophage activation.
Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine, University of Michigan Medical Center, Ann Arbor, Michigan, USA.|Unit for Lung and Airway Research, Physiology Division, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
M A
MA
Kovach
Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine, University of Michigan Medical Center, Ann Arbor, Michigan, USA.
B
B
Singer
Department of Microbiology and Immunology, University of Michigan, Ann Arbor, Michigan, USA.
G
G
Martinez-Colon
Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine, University of Michigan Medical Center, Ann Arbor, Michigan, USA.
M W
MW
Newstead
Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine, University of Michigan Medical Center, Ann Arbor, Michigan, USA.
X
X
Zeng
Department of Nutritional Sciences and School of Public Health, University of Michigan Medical Center, Ann Arbor, Michigan, USA.
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P
Mancuso
Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine, University of Michigan Medical Center, Ann Arbor, Michigan, USA.
T A
TA
Moore
Department of Pathology, University of Michigan Medical Center, Ann Arbor, Michigan, USA.
S L
SL
Kunkel
Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine, University of Michigan Medical Center, Ann Arbor, Michigan, USA.
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M
Peters-Golden
Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine, University of Michigan Medical Center, Ann Arbor, Michigan, USA.|Department of Microbiology and Immunology, University of Michigan, Ann Arbor, Michigan, USA.
B B
BB
Moore
Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine, University of Michigan Medical Center, Ann Arbor, Michigan, USA.
T J
TJ
Standiford
D000328:Adult; D000818:Animals; D002478:Cells, Cultured; D005260:Female; D006801:Humans; D007113:Immunity, Innate; D018928:Immunity, Mucosal; D007375:Interleukin-1 / Q000097:blood* / Q000235:genetics / Q000378:metabolism*; D007710:Klebsiella Infections / Q000276:immunology*; D007711:Klebsiella pneumoniae / Q000502:physiology*; D008168:Lung / Q000276:immunology* / Q000382:microbiology; D008264:Macrophages / Q000276:immunology* / Q000382:microbiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008875:Middle Aged; D011008:Pneumococcal Infections / Q000276:immunology*; D011014:Pneumonia / Q000276:immunology*; D012128:Respiratory Distress Syndrome / Q000276:immunology*; D013296:Streptococcus pneumoniae / Q000502:physiology*; D015854:Up-Regulation
C569167:IL1F9 protein, mouse; C508589:IL36G protein, human; D007375:Interleukin-1