Response by Jia et al to Letter Regarding Article, “Interleukin-35 Promotes Macrophage Survival and Improves Wound Healing After Myocardial Infarction in Mice” (original) (raw)

Circulation Research, 2019

Abstract

Response by Jia et al to Letter Regarding Article, “Interleukin-35 Promotes Macrophage Survival and Improves Wound Healing After Myocardial Infarction in Mice” In Response: We appreciate the comments by Wang et al on our recent publication. In our article, we reveal that IL (interleukin)-35 increases the number of Ly6C macrophages, which is functionally similar to M2-type macrophages. Two highly intriguing articles reported that mouse cardiac macrophage populations could be divided into CCR2 (C-C motif chemokine receptor 2) MHC II (major histocompatibility complex II), CCR2 MHC II, and CCR2 MHC II subsets. We observed that IL-35 could mediate and improve the survival of CCR2 MHC II macrophages, which play crucial roles in various forms of tissue remodeling such as coronary development and postnatal coronary growth. Although we revealed that CD31 was not significantly altered in mice treated with anti–IL-35 antibody compared with its expression in wild-type mice (see Online Figure VII), we cannot completely rule out the possibility that IL-35 contributes to the proliferation of coronary arterial endothelial cells in some way, since CD31 is expressed in both vascular and endocardial endothelial cells. Therefore, future studies are required to explore the mechanisms and the cell-specific effects of IL-35 in coronary arterial endothelial cells using Connexin40-GFP (green fluorescent protein) mice expressing GFP in endothelial cells of coronary arteries, but not veins, capillaries, or endocardium. In addition, more clinical and experimental data are needed to explore the side effects, such us infection incidence, cancer incidence, and mortality post IL-35 treatment and ensure the optimal temporal and spatial treatment option of IL-35 in the setting of myocardial infarction (MI). Immunofluorescence staining of FACS-purified Tregs (see Figure 1) and adoptive transfer of EBI3 (Epstein-Barr virus–induced gene 3) KO and wild-type Tregs (see Figure 4) demonstrate that Tregs-derived IL-35 contributed to the healing process by modulating extracellular matrix deposition and the transition of fibroblasts to myofibroblasts. However, the sources of IL-35 are complex and we are unable to identify the function of certain immune cell population secreting IL-35, as discussed in our article. IL-35–producing inducible regulatory T cells (iTr35 cells) represent unique members of the Treg cell family that were generated by IL-35 and do not express Foxp3 (forkhead box P3). The exact roles of iTr35 cells in MI thus remain elusive and future studies are required to explore the number and function of iTr35 cells after MI. Tregs increased gradually and peaked on day, normalized by 2-week post MI, and subsequently reexpanded in chronic heart failure phase (8 weeks after MI). Tregs change their phenotype in a phasic manner after MI. After acute MI, Treg activation is beneficial and improves cardiac wound healing. However, in chronic ischemic heart failure, Tregs could become dysfunctional and promote adverse left ventricular remodeling. The opposite functions of Tregs in acute and chronic MI period highlighting important differences in immune cell activation and inflammatory profiles. Similarly, the activation of TGF (transforming growth factor)β1 is protective against ischemic myocardial damage during the early phase through improving the replacement of necrotic tissue by a stable collagenous scar and thus preventing left ventricular rupture. However, sustained expression of TGF-β1 is detrimental and could lead to cardiac remodeling and heart failure after MI. In our article, we demonstrate the combination of EBI3 and p35 is increased at day 3, peaked at day 5 and decreased significantly at day 14 post MI, implying that IL-35 promotes TGF-β1 production, contributes to the beneficial effects of Tregs activation and is a central coordinator of wound healing process in the early phase of MI. Future studies are needed to explore the expression and corresponding functional roles of IL-35 in chronic heart failure. Our data indicate that IL-35 reduces cardiac rupture, improves wound healing, and attenuates cardiac remodeling after MI in mice. We agree with the comments by Wang et al that researchers should explore complex mechanisms of IL-35 and the potential benefits and risks of IL-35 treatment in human MI populations. Independent studies and replications from different research laboratories will contribute to the better understanding on the function and therapeutic potentials of IL-35 in MI patients.

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