Alzheimer's disease (AD) and Parkinson's disease (PD) are the two most widespread neurological disorders (NDs) characterized by degeneration of cognitive and motor functions due to malfunction and loss of neurons in the central nervous system (CNS). Numerous evidences have established the role of neuroinflammation in the AD and PD pathology. The inflammatory components such as microglia, astrocytes, complement system and cytokines are linked to neuroinflammation in the CNS. More specifically, cytokines have been found to play a central role in the neuroinflammation of AD and PD. A number of studies have demonstrated abnormally elevated levels of inflammatory cytokines such as interleukin-1β (IL-1β) and tumor necrosis factor (TNF) in AD and PD patients. Activated microglial cells have been shown to be involved in the secretion of pro-inflammatory cytokines such as IL-1, IL-6, TNF-α and transforming growth factor-β, thereby contributing towards the progress of NDs. In addition, studies on AD pathogenesis have demonstrated that microglia produce beta-amyloid protein (Aβ), which by itself is pro-inflammatory and causes activation of several inflammatory components. Similarly, chronic inflammation caused by microglial cells is the fundamental process involved in the destruction of neurons associated with dopamine (DA)-production in the brain of PD patients. Hence, there is a need to explore the key inflammatory components in AD and PD pathogenesis in order to fully understand the root cause and establish a substantial link between these two disorders. Such knowledge will help in better management and treatment of AD and PD.

Tumor-associated macrophages (TAMs) promote tumor progression and inhibit anti-tumor immune response by producing various mediators and preferentially express CD163, CD204, and CD206. However, the role of these TAM subsets in oral squamous cell carcinoma (OSCC) remains unclear. Here we investigated the expression and function of TAM subsets in OSCC, especially in cancer cell proliferation. Biopsy sample from 44 patients with OSCC were examined for the expression of TAM markers and EGF by immunohistochemistry. EGF production of TAM subsets isolated from OSCC patients was assessed by flow cytometry. We also examined the effect of conditioned medium from TAM subsets on the proliferation of OSCC cells. CD163+ cells were detected diffusely all over the tumor and connective tissue area, while CD204+ and CD206+ cells were mainly detected in/around the tumors. Flow cytometric analysis found that CD206+ TAMs strongly produced EGF compared with CD163+ and CD204+ TAMs. Cell proliferation and invasion of OSCC cells cultured with conditioned medium of CD206+ TAMs were strongly enhanced and inhibited by anti-EGFR. The number of CD206+ TAMs positively correlated with worse clinical prognosis. Our results revealed differences in localization and EGF production among these TAM subsets. CD206+ TAMs might play a critical role in the proliferation of OSCC via EGF production.

Hantaviruses, members of the Bunyaviridae family, are emerging category A pathogens that carry three negative stranded RNA molecules as their genome. Hantavirus nucleocapsid protein (N) is encoded by the smallest S segment genomic RNA (viral RNA). N specifically binds mRNA caps and requires four nucleotides adjacent to the cap for high affinity binding. We show that the N peptide has distinct cap-and RNA-binding sites that independently interact with mRNA cap and viral genomic RNA, respectively. In addition, N can simultaneously bind with both mRNA cap and vRNA. N undergoes distinct conformational changes after binding with either mRNA cap or vRNA or both mRNA cap and vRNA simultaneously. Hantavirus RNA-dependent RNA polymerase (RdRp) uses a capped RNA primer for transcription initiation. The capped RNA primer is generated from host cell mRNA by the cap-snatching mechanism and is supposed to anneal with the 3 terminus of vRNA template during transcription initiation by single G-C base pairing. We show that the capped RNA primer binds at the cap-binding site and induces a conformational change in N. The conformationally altered N with a capped primer loaded at the cap-binding site specifically binds the conserved 3 nine nucleotides of vRNA and assists the bound primer to anneal at the 3 terminus. We suggest that the cap-binding site of N, in conjunction with RdRp, plays a key role during the transcription and replication initiation of vRNA genome.Hantaviruses cause two types of serious human illnesses when transmitted to humans from rodent hosts: hemorrhagic fever with renal syndrome and hantavirus cardiopulmonary syndrome (1, 2). The spherical hantavirus particles harbor three negative sense genomic RNA segments (S, L, and M segments) within a lipid bilayer (3). The mRNAs derived from S, L, and M segments encode viral nucleocapsid protein (N), viral RNA-dependent RNA polymerase (RdRp), 2 and glycoproteins (G1 and G2), respectively. The characteristic feature of the hantaviral genome is the partially complementary sequence at the 5Ј and 3Ј termini of each of the three genome segments that undergo base pairing and form panhandle structures (4 -6). N is a multifunctional protein playing a vital role in multiple processes of virus replication cycle and has been found to undergo trimerization both in vivo and in vitro (7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19). During encapsidation, the three viral RNA (vRNA) molecules are specifically recognized by N inside the host cell and targeted for packaging. Multiple in vitro studies have shown that N preferentially binds vRNA compared with complementary RNA (cRNA) or nonviral RNA (13, 20 -25). It has been proposed that the specific binding of N with either the panhandle or the sequence at the 5Ј terminus alone selectively facilitates the encapsidation of vRNA to generate three nucleocapsids that are packaged into infectious virions (25, 26). The RNA-binding domain of Hantaan virus N protein has been mapped to the central conserved region corresponding to amino acids f...

Objective IgG4‐related disease (IgG4‐RD) is a unique inflammatory disorder in which Th2 cytokines promote IgG4 production. In addition, recent studies have implicated the Toll‐like receptor (TLR) pathway. This study was undertaken to examine the expression of TLRs in salivary glands (SGs) from patients with IgG4‐RD. Methods SGs from 15 patients with IgG4‐RD, 15 patients with Sjögren's syndrome (SS), 10 patients with chronic sialadenitis, and 10 healthy controls were examined histologically. TLR family gene expression (TLR‐1 through TLR‐10) was analyzed by DNA microarray in the submandibular glands (SMGs). Up‐regulation of TLRs was confirmed in SGs from patients with IgG4‐RD. Finally, the phenotype of human TLR‐7 (huTLR‐7)–transgenic C57BL/6 mice was assessed before and after stimulation with TLR agonist. Results In patients with IgG4‐RD, TLR‐4, TLR‐7, TLR‐8, and TLR‐9 were overexpressed. Polymerase chain reaction validated the up‐regulation of TLR‐7 in IgG4‐RD compared with the other groups. Immunohistochemical analysis confirmed strong infiltration of TLR‐7–positive cells in the SGs of patients with IgG4‐RD. Double immunohistochemical staining showed that TLR‐7 expression colocalized with CD163+ M2 macrophages. After in vitro stimulation with a TLR‐7 agonist, CD163+ M2 macrophages produced higher levels of interleukin‐33 (IL‐33), which is a Th2‐activating cytokine. In huTLR‐7–transgenic mice, the focus and fibrosis scores in SMGs, pancreas, and lungs were significantly higher than those in wild‐type mice (P < 0.05). Moreover, the concentration of serum IgG, IgG1, and IL‐33 in huTLR‐7–transgenic mice was distinctly increased upon stimulation with a TLR‐7 agonist (P < 0.05). Conclusion TLR‐7–expressing M2 macrophages may promote the activation of Th2 immune responses via IL‐33 secretion in IgG4‐RD.

No abstract