Rodent spleens show a decrease in size after MCAO that appears to be catecholamine (CA)-mediated, but the reason for the change in spleen size after stroke varies between rats and mice. The splenic capsule of rat spleens expresses α
1 adrenergic receptors that cause splenic contraction when activated [
16]. Following permanent MCAO (pMCAO) in rats, circulating CAs cause a transient decrease in spleen size. While the spleen is highly innervated by sympathetic neural networks [
17], denervation of the spleen prior to pMCAO did not prevent the spleen from contracting. However, blocking the α
1 receptors with prazosin or carvedilol did block splenic contraction, whereas propranolol did not block contraction. Carvedilol also decreased infarct size [
18]. Additionally, rat spleens demonstrated a transient decrease in size with the smallest size detected 48 h after pMCAO but a return to pre-stroke size by 72 h. During splenic contraction, splenocytes were released into the systemic circulation and traveled to the injured hemisphere of the brain. Innate splenocytes were found in the brain as early as 48 h, whereas adaptive splenocytes appeared at 96 h following pMCAO [
11]. Generally, there was a negative correlation between spleen size and infarct volume [
19]. Mice also exhibit a significant loss of cells and decreased spleen size following transient MCAO (tMCAO) that persists over time. This loss of splenocytes appears to be due to apoptosis of the splenocytes and loss of splenic structures, including B cell follicles. At 96 h after tMCAO, mice show a 90% reduction in splenocyte numbers compared to sham-operated mice. The greatest effect is on B cells, while T cell numbers appear to increase, specifically regulatory T cells [
20]. An additional study showed that mouse spleens continued to decrease in size through day 7 post-tMCAO [
21]. Mouse spleens are extensively innervated like rat spleens and also appear to highly express α
1-adenergic receptors on the splenic capsule [
22]. Unlike rats, mouse spleens do not contract, but the catecholaminergic innervation of immune cells appears to negatively impact some of these cells resulting in cell death.
In addition to the cellular responses in the spleen to stroke, there are also changes in cytokine and chemokine responses. In mouse spleens, there is an increase by 22 h after tMCAO in TNFα, interferon gamma (IFNγ), IL-6, MCP-1, and IL-2, all of which are pro-inflammatory mediators [
23]. One pro-inflammatory cytokine of interest is IFNγ, since IFNγ
−/− mice have smaller infarcts than wild-type mice [
2]. In rats, splenic increases in IFNγ production as early as 24 h after pMCAO results in a delayed increase in IFNγ in the injured brain at 72 h. This early transient increase in IFNγ in the spleen is likely connected to the later increase in IFNγ in the brain, since splenectomy decreases the IFNγ expression in the brain [
7]. Similar results were found in mice after tMCAO such that IFNγ was increased at 72 h in the brain and splenectomy significantly decreased IFNγ levels within the brain [
8]. IFNγ also initiated the expression of the pro-inflammatory chemokine interferon inducible protein 10 (IP-10) in both the spleen and the brain after pMCAO. Splenectomy prior to pMCAO or treatment with an IFNγ neutralizing antibody after pMCAO reduced IP-10 levels in the brain and subsequent T cell recruitment to the brain [
24].