Inflammatory macrophage phenotype in BTBR T+tf/J mice

Abstract

Although autism is a behaviorally defined disorder, many studies report an association with increased pro-inflammatory cytokine production. Recent characterization of the BTBR T+tf/J (BTBR) inbred mouse strain has revealed several behavioral characteristics including social deficits, repetitive behavior, and atypical vocalizations which may be relevant to autism. We therefore hypothesized that, asocial BTBR mice, which exhibit autism-like behaviors, may have an inflammatory immune profile similar to that observed in children with autism. The objectives of this study were to characterize the myeloid immune profile of BTBR mice and to explore their associations with autism-relevant behaviors. C57BL/6J (C57) mice and BTBR mice were tested for social interest and repetitive self-grooming behavior. Cytokine production was measured in bone-marrow derived macrophages incubated for 24 h in either growth media alone, LPS, IL-4/LPS, or IFNγ/LPS to ascertain any M1/M2 skewing. After LPS stimulation, BTBR macrophages produced higher levels of IL-6, MCP-1, and MIP-1α and lower IL-10 (p < 0.01) than C57 mice, suggesting an exaggerated inflammatory profile. After exposure to IL-4/LPS BTBR macrophages produced less IL-10 (p < 0.01) than C57 macrophages and more IL-12p40 (p < 0.01) suggesting poor M2 polarization. Levels of IL-12(p70) (p < 0.05) were higher in BTBR macrophages after IFNγ/LPS stimulation, suggesting enhanced M1 polarization. We further observed a positive correlation between grooming frequency, and production of IL-12(p40), IL-12p70, IL-6, and TNFα (p < 0.05) after treatment with IFNγ/LPS across both strains. Collectively, these data suggest that the asocial BTBR mouse strain exhibits a more inflammatory, or M1, macrophage profile in comparison to the social C57 strain. We have further demonstrated a relationship between this relative increase in inflammation and repetitive grooming behavior, which may have relevance to repetitive and stereotyped behavior of autism.

Immune Alterations in CD8+ T Cells Are Associated with Neuronal C-C and C-X-C Chemokine Receptor Regulation Through Adenosine A2A Receptor Signaling in a BTBR T+ Itpr3tf/J Autistic Mouse Model

“…BTBR mice have revealed a number of immune abnormalities several of which observed in children with ASD [21]. The neuroimmune relation in the BTBR mice is characterized by higher pro-inflammatory signaling and diminished social interactions [52,53]. BTBR mice showed the elevated expression levels of cytokines in the brain [24].…”

Sensory Integration in Mouse Insular Cortex Reflects GABA Circuit Maturation

“…It is then interesting that somatosensory activation of the IC follows a normal developmental trajectory in BTBR mice, while the maturation of auditory response is aberrant (Figure 3). Given their sub-additive response to conjoint stimulation, self-grooming in these mice may serve to blunt the excessive (potentially ‘painful’) activation of the IC by ambient sound or internal inflammatory cues (Onore et al, 2013). …”

Inflammatory profiles in the BTBR mouse: How relevant are they to autism spectrum disorders?

“…M2 macrophages produce very low levels of IL-12 and high amounts of anti-inflammatory molecules including IL-10 and TGFβ (Sica and Mantovani, 2012). A prominent M1 skewing is evident in BTBR mice, with macrophages from BTBR mice producing significantly more IL-12 and less IL-10 than C57BL/6J mice (Onore et al, 2013). In addition, production of IL-1β by macrophages stimulated under M1 skewing conditions (IFN-γ and LPS) are associated with more impaired social behaviors; increased production of IL-12 in unstimulated cultures was also associated with more severe grooming behaviors, whereas increased production of IL-10 in response to LPS was correlated with less grooming (Onore et al, 2013).…”