Modulation of Macrophage Infiltration and Inflammatory Activity by the Phosphatase SHP-1 in Virus-Induced Demyelinating Disease

Abstract

The protein tyrosine phosphatase SHP-1 is a crucial negative regulator of cytokine signaling and inflammatory gene expression, both in the immune system and in the central nervous system (CNS). Mice genetically lacking SHP-1 (me/me) display severe inflammatory demyelinating disease following inoculation with the Theiler's murine encephalomyelitis virus (TMEV) compared to infected wild-type mice. Therefore, it became essential to investigate the mechanisms of TMEV-induced inflammation in the CNS of SHP-1-deficient mice. Herein, we show that the expression of several genes relevant to inflammatory demyelination in the CNS of infected me/me mice is elevated compared to that in wild-type mice. Furthermore, SHP-1 deficiency led to an abundant and exclusive increase in the infiltration of high-level-CD45-expressing (CD45 hi ) CD11b Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system (CNS) that remains a major cause of disability (76). Several studies demonstrated that MS lesions contain multiple leukocyte cell types, including lymphocytes, macrophages, and dendritic cells, all of which are believed to contribute to lesion formation by various distinct and interacting mechanisms (54, 61). Among these leukocyte subsets, infiltrating macrophages have been identified as major effectors of demyelination in both MS and animal models for MS (17,44,59,102). In accord with these studies, it was recently reported that the dominant mechanism of demyelination in MS is macrophage mediated (15). Indeed, in some models for MS, the requirement for lymphocytes is negligible and macrophages are the sole mediators of demyelination (6, 72).These findings have stimulated intense interest in the function of macrophages in lesion formation, including signaling events that draw these cells into the CNS white matter and trigger the effector mechanisms by which these cells damage myelin. For instance, macrophages have been identified as the major responders to CNS chemokines and producers of a number of proinflammatory cytokines, chemokines, and toxic molecules known to promote demyelination (32,44,63,85,90,91,93,103). Interestingly, both the brains of MS patients and the brains of experimental animals with MS-like diseases contain activated transcription factors like NF-B (34, 40), STAT1 (35,37,40), and STAT6 (18,21,109), which can lead to enhanced expression of these inflammatory molecules. Based on the findings of our previous work, we propose that the modulation of inflammatory signaling via these transcriptional pathways may be deficient in the leukocytes, including the macrophages, of MS patients and that this deficiency is responsible for susceptibility to inflammatory demyelinating processes within the CNS.SHP-1 is a protein tyrosine phosphatase with two Src homology 2 domains which acts as a negative regulator of both innate and acquired immune cytokine signaling via NF-B (52, 67), STAT1 (29,68), and STAT6 (13,43,45,50). Mice genetically lacking SHP-1 (motheaten mice) display myelin de...

β-Sitosterol down-regulates some pro-inflammatory signal transduction pathways by increasing the activity of tyrosine phosphatase SHP-1 in J774A.1 murine macrophages

“…In the present study, a more robust effect of SIT on the activity of the SHP-1 enzyme compared to PP2A was observed, even at lower physiological levels. The importance of SHP-1 as a regulator of both STAT and NF-κB pathways is well documented [25,30]. In the case of that STAT pathway, SHP-1 acts as a negative regulator of the JAK/STAT pathway by dephosphorylating the activated JAK and/or STAT and thus reducing inflammation [31,32].…”

“…Furthermore, mice devoid of SHP-1 (moth-eaten mice) display an autoimmune hyper-inflammatory phenotype [25,33] and are highly susceptible to development of EAE [25]. Thus, it has been proposed that decreased SHP-1 activity may propagate inflammatory diseases by allowing over expression of phosphorylated STAT1 and NF-κB translocation [24,25,30,33].…”

“…SHP-1 is an SH-2 containing tyrosine phosphatase which has been shown to decrease activation by dephosphorylation of STATs, particularly STAT1 [22,23]. Christophi and others have recently shown that humans with MS and mice with EAE are deficient in SHP-1 [24,25]. Moreover, SHP-1 knockout mice (moth eaten mice) exhibit a hyper-inflammatory response to insult [26].…”

CD300F Blocks Both MyD88 and TRIF-Mediated TLR Signaling through Activation of Src Homology Region 2 Domain-Containing Phosphatase 1

“…In lymphocytes and myeloid cells, SHP-1 has been demonstrated to modulate cellular signals that involve PI3K, Janus kinase 2, STATs, MAPKs, ERK, and NF-kB (35,36). As a result, SHP-1 deficiency resulted in enhanced macrophage activities in clinical cases and experimental models (37)(38)(39). Phosphorylation of CD300F and its subsequent interaction with SHP-1 lead to the phosphorylation and activation of SHP-1.…”

Prevention of Both Neutrophil and Monocyte Recruitment Promotes Recovery after Spinal Cord Injury

“…Monocytes, sources of cytokines, chemokines (Christophi et al, 2009;Kigerl et al, 2009) and oxidative stress (Laskin, 2009), infiltrate the cord, beginning as early as 24 h post-injury (Letellier et al, 2010), reaching peak levels between 4 and 7 days (Beck et al, 2010). Animals, treated systemically with clodronate liposomes to deplete these monocytes, show an improvement in neurological recovery after SCI (Popovich et al, 1999).…”