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Published on: June 23, 2013

Alternatively activated macrophage-derived RELM-{alpha} is a negative regulator of type 2 inflammation in the lung

Meera G Nair1, Yurong Du, Jacqueline G Perrigoue

  • 1Department of Pathobiology, University of Pennsylvania, Philadelphia, 19104, USA.

The Journal of Experimental Medicine
|April 8, 2009
PubMed

Insights

Resistin-like molecule alpha (RELM-alpha) limits lung inflammation by regulating T helper 2 cell responses. RELM-alpha deficiency in alternatively activated macrophages exacerbates allergic lung inflammation and fibrosis.

Area of Science:

  • Immunology
  • Inflammation research
  • Macrophage biology

Background:

  • Alternatively activated macrophages (AAMacs) are key in inflammatory diseases.
  • Molecules like resistin-like molecule alpha (RELM-alpha) define AAMacs, but their role in disease is unclear.
  • RELM-alpha's influence on inflammatory disease development, progression, and resolution requires investigation.

Purpose of the Study:

  • To investigate the immunoregulatory role of RELM-alpha in T helper type 2 (Th2) cytokine-dependent lung inflammation.
  • To characterize the impact of RELM-alpha deficiency on the development and severity of allergic lung inflammation.
  • To elucidate the mechanisms by which RELM-alpha modulates immune responses in the context of lung inflammation.

Main Methods:

  • Generation of RELM-alpha-deficient (Retnla(-/-)) mice.
  • Utilized a mouse model of Schistosoma mansoni (Sm) egg-induced Th2 lung inflammation.
  • Assessed lung inflammation, granuloma formation, fibrosis, pulmonary vascularization, and CD4(+) T cell cytokine production.
  • Investigated the binding of recombinant RELM-alpha to immune cells and its effect on cytokine production via Bruton's tyrosine kinase (BTK) signaling.
  • Evaluated the capacity of Retnla(-/-) AAMacs to promote Th2 cell differentiation.

Main Results:

  • Retnla(-/-) mice exhibited exacerbated lung inflammation, increased pulmonary vascularization, larger granulomas, and elevated fibrosis following Sm egg challenge compared to wild-type mice.
  • Increased disease severity in Retnla(-/-) mice was associated with elevated expression of Th2 cytokines from CD4(+) T cells.
  • Recombinant RELM-alpha inhibited Th2 cytokine production by macrophages and CD4(+) T cells in a BTK-dependent manner.
  • AAMacs from Retnla(-/-) mice promoted exaggerated antigen-specific Th2 cell differentiation.

Conclusions:

  • RELM-alpha, produced by AAMacs, plays a critical immunoregulatory role in limiting Th2 cytokine-mediated pulmonary inflammation.
  • RELM-alpha acts, in part, by regulating CD4(+) T cell responses and inhibiting Th2 cytokine production.
  • Loss of RELM-alpha leads to exaggerated allergic lung inflammation and fibrosis, highlighting its protective function.

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