Optineurin is a multifunctional polyubiquitin-binding protein implicated in autophagy and inflammatory signalling, processes that have been described as pathogenic mechanisms in neurodegenerative diseases. Notably, more than 40 mutations in the OPTN gene, which encodes for optineurin, were linked to amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), neurodegenerations marked with excessive motor neurons loss, loss of neurons from frontal and temporal lobes, chronic inflammation, and protein aggregation in the central nervous system (CNS). However, the pathogenic role of optineurin mutations is still largely unclear. The autopsies of ALS and FTD patients carrying the optineurin mutations show TAR DNAbinding protein 43 (TDP-43) aggregates, which could elicit its nuclear depletion and lossof-function. Since optineurin acts as an adaptor protein in autophagy and inflammatory signalling, and chronic inflammation could exacerbate TDP-43 aggregation, here we tested if optineurin ALS-mimicking mutations could lead to impaired TDP-43 proteostasis, excessive inflammation, and/or inefficient immune responses. Moreover, as ageing is a major risk factor for ALS and FTD, and untreated young mice carrying optineurin ALS-linked mutations do not develop the disease, here we investigated whether ageing could trigger neurological, neuropathological, and/or immunological alterations. To this end, we used (1) Optn470T mouse model, that mimics loss-of-function Q398X truncation found in ALS patients both of which express a lower level of truncated optineurin (henceforth termed optineurin insufficiency) and (2) optineurin deficient microglial BV2 cells made using CRISPR/Cas9 technology (BV2 Optn KO). We found elevated basal TDP-43 protein levels in primary mouse Optn470T myeloid cells and cortical neurons, which were post-translationally regulated. Moreover, we demonstrated that optineurin deficiency did not sensitize cells to apoptosis upon autophagy inhibition and that TDP-43 accumulation in Optn470T primary microglia was not caused by an autophagy block. In contrast, we showed that optineurin insufficiency caused an altered TDP-43 turnover, which was unaffected by experimental block in autophagy in both bone marrow-derived macrophages (BMDMs) and primary neurons. To further evaluate the role of optineurin in inflammation and TDP-43 accumulation, we stimulated BV2 cell lines and primary microglia with lipopolysaccharide (LPS) to mimic bacterial infection. We observed a significant increase in TDP-43 protein levels in WT cells without changes in optineurin levels. However, LPS failed to increase already elevated TDP-43 levels in untreated optineurin-deficient and-insufficient myeloid cells, suggesting that they already reached a plateau at basal conditions. Moreover, we demonstrated no nuclear depletion or aggregation of TDP-43 in Optn470T primary microglia in basal state or with LPS. Characterization of aged Optn470T mice did not show motor or cognitive defects, or differential TDP-43 insolubility in the whole-brain lysates compared to WT mice. In addition, we demonstrated enhanced expression of certain cytokines and chemokines in the CNS during ageing, but with neglectable differences between old WT and Optn470T mice. Moreover, spleen immunophenotyping uncovered signs of ageing of the immune system (inflammageing and immunosenescence) in old Optn470T mice that were comparable to WT mice. These included an increase in memory and regulatory T lymphocytes, a drop in naïve T lymphocytes, and an increase in the number of macrophages and neutrophils. However, we showed that macrophages and conventional dendritic cells (cDC) exhibited increased expression of activation markers in old Optn470T mice, although we could not link it to any phenotype. Altogether, a combination of ageing and optineurin insufficiency did not induce ALS and/or FTD-like immune imbalance and neuropathology in mice. To further evaluate crosstalk between optineurin insufficiency and TDP-43 we established a new two-hit ALS and/or FTD model by crossing Optn470T mice with the transgenic mice carrying a human TDP-43 patient mutation (G348C) but did not observe an ALS-like phenotype either. In conclusion, we showed TDP-43 accumulation in optineurin-insufficient neurons and microglia. In microglia, the accumulation was not caused by an autophagy block, and it was unresponsive to inflammation, while in neurons it was likely caused by a block in autophagy. Furthermore, the Optn470T mouse model during ageing, even when crossed to mutant transgenic TDP-43 did not show motor or cognitive defects, TDP-43 aggregation, or immunological alterations typical for ALS and/or FTD. Thus, further research is necessary to elucidate the mechanistic links between optineurin mutations and TDP-43-mediated pathology.