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. 2015 Feb 1;194(3):863-7.
doi: 10.4049/jimmunol.1402534. Epub 2014 Dec 24.

Cutting edge: maresin-1 engages regulatory T cells to limit type 2 innate lymphoid cell activation and promote resolution of lung inflammation

Nandini Krishnamoorthy  1 , Patrick R Burkett  2 , Jesmond Dalli  3 , Raja-Elie E Abdulnour  1 , Romain Colas  3 , Sesquile Ramon  4 , Richard P Phipps  5 , Nicos A Petasis  6 , Vijay K Kuchroo  7 , Charles N Serhan  3 , Bruce D Levy  8
Affiliations

Cutting edge: maresin-1 engages regulatory T cells to limit type 2 innate lymphoid cell activation and promote resolution of lung inflammation

Nandini Krishnamoorthy et al. J Immunol. .

Abstract

Asthma is a chronic inflammatory disease that fails to resolve. Recently, a key role for type 2 innate lymphoid cells (ILC2s) was linked to asthma pathogenesis; however, mechanisms for ILC2 regulation remain to be determined. In this study, metabololipidomics of murine lungs identified temporal changes in endogenous maresin 1 (MaR1) during self-limited allergic inflammation. Exogenous MaR1 reduced lung inflammation and ILC2 expression of IL-5 and IL-13 and increased amphiregulin. MaR1 augmented de novo generation of regulatory T cells (Tregs), which interacted with ILC2s to markedly suppress cytokine production in a TGF-β-dependent manner. Ab-mediated depletion of Tregs interrupted MaR1 control of ILC2 expression of IL-13 in vivo. Together, the findings uncover Tregs as potent regulators of ILC2 activation; MaR1 targets Tregs and ILC2s to restrain allergic lung inflammation, suggesting MaR1 as the basis for a new proresolving therapeutic approach to asthma and other chronic inflammatory diseases.

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Figures

Figure 1
Figure 1. Maresin 1 is temporally regulated during allergic inflammation
(A) (Upper Panel) Representative multiple reaction trace for MaR1 (m/z = 359-250) (Lower Panel) MS/MS spectrum employed in the identification of MaR1. (B) Lung MaR1 levels measured during allergic inflammation. (A) and (B) Results are mean ± SD and are representative of two independent experiments (n=3 mice per time point). (C) Cell differentials in BALF, (D) Histology of hematoxylin and eosin–stained lung tissue, 40X. (E) OVA-specific IgE measured in serum. (F) Cytokines in BALF measured by ELISA. Results are mean ± SD and are representative of four independent experiments (n>3 mice per group).
Figure 2
Figure 2. Maresin 1 promotes de novo generation of Foxp3-expressing Tregs
(A)% CD3 and Tregs (CD4+F+) in lungs (B) DO11.10 CD4+ T (depleted of natural Tregs) cells were adoptively transferred into sensitized mice prior to aerosol challenge. Antigen-specific Tregs were analyzed by flow cytometry. (C) Tregs generation from naïve CD4+ T cells. (D) Amphiregulin production measured by ELISA (right panel). Results are mean ± SD and are representative of three independent experiments with duplicate determinations by ELISA. (E) Flow cytometry of cytokine production by ILC from allergic inflammation model. Plots are gated for ILC2 (Lin−CD45+Thy1.2+CD25+) (F) IL-13 and IL-5 (left panel) and amphiregulin concentrations (right panel) from supernatants of lungs cells. (A, B, E, F) Results are mean ± SD and are representative of three independent experiments (n>3 mice per group).
Figure 3
Figure 3. Maresin 1 and Tregs regulates cytokine production from ILC2
(A) Lung ILCs were sorted from mice following allergic inflammation. EGFP+Tregs from lungs of naïve mice were added in titrated ratios to specific wells. IL-13 levels were measured 72h by ELISA (B) Lung ILC and EGFP+ Tregs were sorted from sensitized mice exposed to vehicle or MaR1 just prior to allergen challenge. The ILCs were cultured in the absence or presence of Tregs for 72h. IL-13 production was measured by ELISA. ND (not detected). Results are mean ± SD and are representative of three independent experiments with duplicate determinations. (C) Foxp3 expression on CD4 T cells (left panel) and IL-13 (right panel) production in lungs ILC2 following administration of anti-CD25 or isotype control was analyzed by flow cytometry. Results are mean ± SD and are representative of two independent experiments (n>3 mice per group).
Figure 4
Figure 4. Maresin 1 accelerates the resolution of allergic inflammation
Inflammation analyzed on day 21 of protocol (A) Leukocyte differential counts of BALF cells were performed. (B) Histology of hematoxylin and eosin–stained lung tissue, 40x. (C) Type 2 cytokines and TGF-β levels in the lung BALF measured by ELISA. (D,E) IL-13 and IL-5 cytokine production by ILC2 analyzed by flow cytometry. (F) Lung Treg expression analyzed by flow cytometry. Results are mean ± SD and are representative of three independent experiments (n>3 mice per group).
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