Ya-Ling Chan

TIAM Rac1‐associated GEF 2 short form (TIAM2S) as an oncoprotein alters the immunity of peripheral immune cells to construct an inflammatory tumor microenvironment. However, its role in the activation of microglia, the primary innate immune cells of the brain, and neuroinflammation remains unknown. This study investigated the mechanism underlying TIAM2S shapes immune properties of microglia to facilitate neuron damage. Human microglial clone 3 cell line (HMC3) and human brain samples were applied to determine the presence of TIAM2S in microglia by western blots and double immunostaining. Furthermore, TIAM2S transgenic mice combined with multiple reconstituted primary neuron–glial culture systems and a cytokine array were performed to explore how TIAM2S shaped immune priming of microglia and participated in lipopolysaccharide (LPS)‐induced neuron damage. TIAM2S protein was detectable in HMC3 cells and presented in a small portion (~11.1%) of microglia in human brains referred to as TIAM2S‐positive microglia. With the property of secreted soluble factor‐mediated immune priming, TIAM2S‐positive microglia enhanced LPS‐induced neuroinflammation and neural damage in vivo and in vitro. The gain‐ and loss‐of‐function experiments showed soluble intercellular adhesion molecule‐1 (sICAM‐1) participated in neurotoxic immune priming of TIAM2S+ microglia. Together, this study demonstrated a novel TIAM2S‐positive microglia subpopulation enhances inflammation and neurotoxicity through sICAM‐1‐mediated immune priming.

The short isoform of human TIAM2 has been shown to promote proliferation and invasion in various cancer cells. However, the roles of TIAM2S in immune cells in relation to tumor development have not been investigated. To characterize the effects of TIAM2S, we generated TIAM2S-overexpressing mouse lines and found that aged TIAM2S-transgenic (TIAM2S-TG) developed significantly higher occurrence of lymphocytic infiltration and tumorigenesis in various organs, including colon. In addition, TIAM2S-TG is more sensitized to AOM-induced colon tumor development, suggesting a priming effect toward tumorigenesis. In the light of our recent findings that TIAM2S functions as a novel regulator of cellular serotonin level, we found that serotonin, in addition to Cox2, is a unique inflammation marker presented in the colonic lesion sites in the aged TG animals. Furthermore, our results demonstrated that ectopic TIAM2S altered immunity via the expansion of T lymphocytes; this was especially pronounced in CD8⁺ T cells in combination with CXCL13/BCA-1 pro-inflammatory chemokine in the serum of TIAM2S-TG mice. Consequently, T lymphocytes and B cells were recruited to the lesion sites and stimulated IL-23/IL17A expression to form the tertiary lymphoid organs. Collectively, our research suggests that TIAM2S provokes a pro-inflammatory immune microenvironment permissive to colorectal tumorigenesis through the serotonin-induced immunomodulatory effects.

TIAM2S, the short form of human T‐cell lymphoma invasion and metastasis 2, can have oncogenic effects when aberrantly expressed in the liver or lungs. However, it is also abundant in healthy, non‐neoplastic brain tissue, in which its primary function is still unknown. Here, we examined the neurobiological and behavioral significance of human TIAM2S using the human brain protein panels, a human NT2/D1‐derived neuronal cell line model (NT2/N), and transgenic mice that overexpress human TIAM2S (TIAM2S‐TG). Our data reveal that TIAM2S exists primarily in neurons of the restricted brain areas around the limbic system and in well‐differentiated NT2/N cells. Functional studies revealed that TIAM2S has no guanine nucleotide exchange factor (GEF) activity and is mainly located in the nucleus. Furthermore, whole‐transcriptome and enrichment analysis with total RNA sequencing revealed that TIAM2S‐knockdown (TIAM2S‐KD) was strongly associated with the cellular processes of the brain structural development and differentiation, serotonin‐related signaling, and the diseases markers representing neurobehavioral developmental disorders. Moreover, TIAM2S‐KD cells display decreased neurite outgrowth and reduced serotonin levels. Moreover, TIAM2S overexpressing TG mice show increased number and length of serotonergic fibers at early postnatal stage, results in higher serotonin levels at both the serum and brain regions, and higher neuroplasticity and hyperlocomotion in latter adulthood. Taken together, our results illustrate the non‐oncogenic functions of human TIAM2S and demonstrate that TIAM2S is a novel regulator of serotonin level, brain neuroplasticity, and locomotion behavior.