BLT1-dependent Alveolar Recruitment of CD4(+)CD25(+) Foxp3(+) Regulatory T Cells is Important for Resolution of Acute Lung Injury

Rationale: Recent study has demonstrated that CD4(+)CD25(+)Foxp3(+) regulatory T cells (Tregs) present in bronchoalveolar lavage fluid (BALF) contribute to the resolution of an experimental acute lung injury (ALI). However, the molecular mechanism underlying the alveolar recruitment of Treg remains unclear.

Objectives: To determine the role of BLT1, a chemotactic receptor for leukotriene B4 (LTB4), in Treg recruitment to BALF of LPS-induced ALI.

Methods: We examined BLT1 expression in mouse and human Tregs and evaluated its role in mediating Treg migration in vitro and in vivo.

Measurements And Main Results: We found that BLT1 expression was strongly up-regulated in Tregs on activation, and that BLT1 mediated the migration of activated, but not resting, Tregs toward LTB4 in vitro. LTB4 levels were persistently elevated in BALF of LPS-induced ALI. Blockade of LTB4-BLT1 pathway by administrating antagonists 1 day after LPS exposure significantly decreased BALF Treg numbers and impaired resolution of ALI characterized by persistent BALF protein, neutrophilic infiltrates, and elevated proinflammatory cytokines. Furthermore, there were significantly less BLT1(-/-) Tregs than wild-type Tregs migrating to BALF of LPS-exposed recipient Rag-1(-/-) mice after adoptive transfer (point estimate 299.73; 95% confidence interval, 255.77-343.69; P < 0.00001), and the impaired alveolar recruitment of BLT1(-/-) Tregs caused the inability to restore the resolution of ALI.

Conclusions: Our findings reveal a novel antiinflammatory role of BLT1 in the resolution of ALI by mediating the alveolar recruitment of Tregs, and indicate that therapies aimed at interrupting the LTB4-BLT1 pathway after ALI onset could be harmful to the resolution of ALI.