IL-10 Deficiency Exacerbates the Brain Inflammatory Response to Permanent Ischemia without Preventing Resolution of the Lesion

Abstract

Stroke induces inflammation that can aggravate brain damage. This work examines whether interleukin-10 (IL-10) deficiency exacerbates inflammation and worsens the outcome of permanent middle cerebral artery occlusion (pMCAO). Expression of IL-10 and IL-10 receptor (IL-10R) increased after ischemia. From day 4, reactive astrocytes showed strong IL-10R immunoreactivity. Interleukin-10 knockout (IL-10 KO) mice kept in conventional housing showed more mortality after pMCAO than the wild type (WT). This effect was associated with the presence of signs of colitis in the IL-10 KO mice, suggesting that ongoing systemic inflammation was a confounding factor. In a pathogen-free environment, IL-10 deficiency slightly increased infarct volume and neurologic deficits. Induction of proinflammatory molecules in the IL-10 KO brain was similar to that in the WT 6 hours after ischemia, but was higher at day 4, while differences decreased at day 7. Deficiency of IL-10 promoted the presence of more mature phagocytic cells in the ischemic tissue, and enhanced the expression of M2 markers and the T-cell inhibitory molecule CTLA-4. These findings agree with a role of IL-10 in attenuating local inflammatory reactions, but do not support an essential function of IL-10 in lesion resolution. Upregulation of alternative immunosuppressive molecules after brain ischemia can compensate, at least in part, the absence of IL-10.

Antigen Presentation After Stroke

“…The mechanisms by which systemic inflammation exhacerbates cerebral ischemia are diverse, including reduced reperfusion after vessel recanalization [105], increased BBB injury, and edema formation [106]. Raising systemic inflammation in experimental ischemia through IL-1β administration, or in IL-10-deficient mice, or in mice with chronic infection that have a T helper 1 (Th1)-polarized immune response, has been associated to increased disruption of tight junction proteins and basal lamina collagen, increased platelet aggregation, microvascular injury, increased MMP activation, and increased mortality after experimental ischemia [102,107,108]. Tight junctions between endothelial cells and the epithelial cells of the blood-CSF barrier limit access to the CNS by circulating cells [109], but activated T cells can enter to the CNS in inflammatory situations because they express adhesion molecules, chemokine receptors, and integrins [110].…”

Roles of Pro- and Anti-inflammatory Cytokines in Traumatic Brain Injury and Acute Ischemic Stroke

“…IL-10 plays an important role in neuroprotection post-stroke, as IL-10 knockout mice do not improve histologically with administration of the anti-inlammatory cytokine IL-33 post-AIS (158). Furthermore, IL-10 knockout mice have an exacerbated, delayed inlammatory response with higher mRNA levels of TNF-α, IL-1β, MMP-9, and COX-2 at day 4 post-AIS, whereas wildtype mice express high IL-10 and IL-10R levels at this time point [175]. Studies show that decreased levels of IL-10 are associated with poor stroke outcomes and that administration of IL-10 post-stroke helps to reduce poor histological and behavioral outcomes [17,[175][176][177][178][179].…”

“…Furthermore, IL-10 knockout mice have an exacerbated, delayed inlammatory response with higher mRNA levels of TNF-α, IL-1β, MMP-9, and COX-2 at day 4 post-AIS, whereas wildtype mice express high IL-10 and IL-10R levels at this time point [175]. Studies show that decreased levels of IL-10 are associated with poor stroke outcomes and that administration of IL-10 post-stroke helps to reduce poor histological and behavioral outcomes [17,[175][176][177][178][179]. However, IL-10 knockout mice have been shown to induce a degree of immunosuppression post-AIS with higher levels of T-cell inhibitory CTLA-4 mRNA, phagocytic macrophages, and the M2 microglia marker arginase-1 at day 4 post-stroke [175].…”

“…IL-10 and IL-10R mRNA levels increase post-AIS with IL-10Rs noted on astrocytes in the infarct zone where astrocytes atempt to wall of the lesion site from viable surrounding tissue [175]. IL-10 plays an important role in neuroprotection post-stroke, as IL-10 knockout mice do not improve histologically with administration of the anti-inlammatory cytokine IL-33 post-AIS (158).…”

Neuroinflammation: Peripheral and Neurogenic Underlying Processes

“…In spite of this, microglial M2 has several immunomodulatory functions: it releases the anti-inflammatory cytokine IL-10 and expresses Arginase 1 (Arg1), which competes with iNOS during the effector immune response (Cherry et al, 2014). During NI, on the other side, the presence of M2 microglia attenuates the disease severity as seen in ischemic shock, Alzheimer, and spinal cord injury due to its ability to control exacerbate immune responses (Kigerl et al, 2009;Perez-de Puig et al, 2013;Yamanaka et al, 2012). It is also likely that M2 microglia may control the recruitment of peripheral cells and the activation of effector cells (Jiang et al, 2012).…”