Mast cell–derived TNF can promote Th17 cell–dependent neutrophil recruitment in ovalbumin-challenged OTII mice

Abstract

IntroductionSeveral proinflammatory cytokines, including TNF, IL-1, and IL-17, can directly induce neutrophil recruitment. For example, inhalation of recombinant TNF, IL-1, or IL-17 can provoke neutrophil infiltration into the airways. [1][2][3] These cytokines can also play important roles in the pulmonary neutrophilia induced by infection with the Gram-negative bacteria Klebsiella pneumoniae, and can contribute to bacterial clearance. [4][5][6] However, both the roles of these proinflammatory cytokines, and the most important cellular sources of their production, can vary according to the models of inflammation analyzed. For example, in mice, mast cell-derived TNF has been reported to contribute importantly to neutrophil recruitment and host defense against K. pneumoniae. 7 By contrast, it has been reported that 8,9 but neither TNF nor IL-1, 10 is important for the pulmonary neutrophilia induced by LPS, a component of Gram-negative bacteria.To date, no reports have investigated the possible role of mast cells in the development of T helper 17 (Th17) cell-dependent, neutrophil-rich inflammatory responses, either in the airways or in other anatomical sites. To address this question, we decided to use a model of protein antigen (Ag) (ovalbumin [OVA])-induced neutrophil-predominant airway inflammation in OVA-specific T-cell receptor (TCR)-expressing mice. We took this approach because of reports indicating that OVA challenge can induce neutrophil-rich airway inflammation in OVA-specific TCR-expressing BALB/c-DO11.10 mice, 11,12 and that IL-17 is required for the induction of airway hyperreactivity (AHR) in this model. 13 However, we elected to use OVA-specific TCR-expressing C57BL/6-OTII mice, 14 instead of BALB/c-DO11.10 mice, for the work reported herein. C57BL/6-OTII mice are on the same strain background as mice that are either profoundly deficient in mast cells, lack the FcR␥ chain (that is required for the activation of mast cells via either the Fc⑀RI or Fc␥RIII that are expressed on their surface 15,16 ), or lack IL-17 or any of several other specific cytokines or cytokine receptors. Therefore, by working with C57BL/6-OTII mice, we were able to use a genetic approach to investigate in detail the importance of each of these candidate elements in the airway neutrophil infiltration elicited by OVA challenge in this model. Materials and methods Experimental approachWe first established and characterized a model of OVA-induced neutrophilrich airway inflammation in OVA-specific TCR-expressing C57BL/6-OTII mice. We then used a combination of pharmacologic and genetic approaches to investigate the potential roles of individual mediators, cytokines, and chemoattractants in the development of the neutrophil-rich airway inflammation induced by Ag challenge in this model. Finally, we used a genetic approach to investigate the roles of FcR␥, mast cells, and mast cell-derived TNF in this model of Ag-and Th17 cell-dependent, neutrophil-rich airway inflammation. The online version of this article contains a data supplement...

Immunomodulatory mast cells: negative, as well as positive, regulators of immunity

“…Some of the positive immunomodulatory functions of mast cells that have been proposed based on in vitro studies have been confirmed in vivo using mast cell knock-in mice 1,54,[57][58][59][60][61][62][63][64][65][66][67][68][69][70] or in mice lacking specific mast-cell-associated proteases [26][27][28][32][33][34] or lacking specific protease enzymatic activity 11 (Table 1 ). In many of these studies, the end points assessed included the recruitment of particular immune cells, such as granulocytes 28,32,33,[57][58][59][60][61]63,64,[67][68][69][70] , DCs 62,64,65,71 or various subpopulations of lymphocytes 64,67,70,72 .…”

“…In many of these studies, the end points assessed included the recruitment of particular immune cells, such as granulocytes 28,32,33,[57][58][59][60][61]63,64,[67][68][69][70] , DCs 62,64,65,71 or various subpopulations of lymphocytes 64,67,70,72 . Many of these studies also demonstrated that the lack of mast cells 54,[57][58][59][60][61][62][63][64]67,69,70 or a specific mast-cell product 28,32,33,54,60,63,67,68,70 also reduced the pathology associated with the immune response or impaired its effectiveness in promoting host resistance to infection.…”

“…67 ). Mast cells also can contribute substantially to the disease pathology in models of autoantibody-induced destructive arthritis 80 , bullous pemphigoid (an autoimmune disease of the skin) 81 and in a model of T H 17-cell-dependent, neutrophil-associated lung inflammation 68 .…”

Role of Mast Cells in Progressive Renal Diseases

“…101 They also influence T cell differentiation: IL-4 and histamine direct Th 2 responses 102 as well as modulate the differentiation of Th17 ϩ CD4 cells. 103 It is in the generation of effector responses, however, where mast cells may have the greatest impact. Mast cells in the periphery enhance effector T cell recruitment directly by the production of chemoattractants.…”

Is there a role for mast cells in psoriasis?

“…The adhesion molecules on mast cells, especially ICAM-1, can interact with T cells leading to T cell activation, but on the other hand mast cells can also be activated upon cell-cell contact with activated T cells resulting in enhanced mast cell degranulation, migration and adhesion to extracellular matrix and endothelial cell ligands [12]. In recent experiments with mice, mast cells and their TNF have been reported to enhance antigen-and Th17 celldependent development of a neutrophil-rich inXammatory response in airways [126] suggesting that mast cells can promote Th17 cell-dependent inXammation in vivo. In addition to local actions in the skin previous Wndings in mice show that as a result of dinitroXuorobenzene-induced contact hypersensitivity mast cells are activated and they migrate to draining lymph nodes wherein they can mediate T cell recruitment [198].…”