Protective role of NKT cells and macrophage M2-driven phenotype in bleomycin-induced pulmonary fibrosis

Abstract

Pulmonary fibrosis is a result of an abnormal wound healing in lung tissue triggered by an excessive accumulation of extracellular matrix proteins, loss of tissue elasticity, and debit of ventilatory function. NKT cells are a major source of Th1 and Th2 cytokines and may be crucial in the polarization of M1/M2 macrophages in pulmonary fibrogenesis. Although there appears to be constant scientific progress in that field, pulmonary fibrosis still exhibits no current cure. From these facts, we hypothesized that NKT cells could influence the development of pulmonary fibrosis via modulation of macrophage activation. Wild type (WT) and NKT type I cell-deficient mice (Jα18) were subjected to the protocol of bleomycin-induced pulmonary fibrosis with or without treatment with NKT cell agonists α-galactosylceramide and sulfatide. The participation of different cell populations, collagen deposition, and protein levels of different cytokines involved in inflammation and fibrosis was evaluated. The results indicate a benign role of NKT cells in Jα18 mice and in wild-type α-galactosylceramide-sulfatide-treated groups. These animals presented lower levels of collagen deposition, fibrogenic molecules such as TGF-β and vimentin and improved survival rates. In contrast, WT mice developed a Th2-driven response augmenting IL-4, 5, and 13 protein synthesis and increased collagen deposition. Furthermore, the arginase-1 metabolic pathway was downregulated in wild-type NKT-activated and knockout mice indicating lower activity of M2 macrophages in lung tissue. Hence, our data suggest that NKT cells play a protective role in this experimental model by down modulating the Th2 milieu, inhibiting M2 polarization and finally preventing fibrosis.

Inflammasome Is Activated in the Liver of Cholestatic Patients and Aggravates Hepatic Injury in Bile Duct–Ligated Mouse

“…The increase in Il-4 is known to lead to stimulation of Tgf-b1 expression, a classic profibrotic cytokine. [16][17][18] This would explain why fibrosis was increased in Casp1 -/-BDL livers, as illustrated in Figure 7. The reduced hepatic injury seen in Casp1 -/-BDL mice (absence of the inflammasome) is also consistent with several earlier reports in which depletion of macrophages attenuated liver injury in rodent models of cholestasis.…”

Macrophages: friend or foe in idiopathic pulmonary fibrosis?

“…Interestingly, Tregs lack of Tim-3 are noted to repress the expression of p-STAT3, thereby attenuating the induction of M2 macrophages in acute respiratory distress syndrome (ARDS)-associated pulmonary fibroproliferation [ 101 ]. Similarly, natural killer T cells (NKTs), a subset of T lymphocytes expressing membrane receptors from both T and NK lineages [ 102 ], can mediate a protective effect against fibrosis by inhibiting a Th2 response and preventing M2 macrophage polarization [ 103 ] in the bleomycin animal model.…”

The Impact of Invariant NKT Cells in Sterile Inflammation: The Possible Contribution of the Alarmin/Cytokine IL-33

“…As regards iNKT cells, one may presume that their functional malleability renders them capable of intervening not only in initiation but also in the resolution of sterile inflammation. However, few studies have described the role of iNKT cells in the resolution of sterile inflammation ( 24 , 26 , 27 , 55 ) (Table 1 ). For example, in experimental models of acute liver injury (IRI ( 9 , 10 ) and ConcanavalinA (ConA)-induced hepatitis ( 56 , 57 ), iNKT cells display a pro-inflammatory deleterious phenotype.…”

“…Interestingly, this mechanism is similar to a reported model of sterile inflammation in the peritoneum ( 55 ). However, IFN-γ-producing iNKT cells, rather than their IL-4-producing counterparts, are resolving in several models of sterile inflammation in the lung ( 26 – 28 ) (Table 1 ). Taken together, these data reveal that iNKT cell functions required to resolve sterile inflammation and to promote tissue repair strongly depend on the organ microenvironment.…”