This is a well written review on a very important topic for equine health. The equine MPS plays an important role in many diseases in the horse and an overview of the current knowledge of this system in the horse is timely and provides important insights for future research.

The title of the review and the abstract and content of the manuscript do not completely match. The authors describe the equine MPS in different tissues. They also make a comparison with the murine and human MPS; although useful, in general the description of especially the murine MPS is often times too detailed and too extensive.
The authors aim to provide a review of the equine MPS system; the title should reflect that. One of the conclusions from the description can be that the equine MPS can serve as a model for the human MPS and diseases that affect the innate immune system in people. The question is if that should be in the title since the major focus of the review is the description of the equine MPS.

In my view the review would benefit from a re-focus. A description of the current state of knowledge of the equine MPS with reference to evidence in other relevant species. In several sections of the manuscript, a detailed description of the murine (and human) MPS is followed by a description of the equine MPS. In other sections these species-specific descriptions are interweaved, putting findings in the horse into context. This context is often lacking when description of the MPS in other species precedes the equine MPS description.
As an example: where the description of the BMDM focus on the horse primarily, the description of the macrophages in the GI-tract start with an extensive description of the MPS in mice and humans. Albeit important, I believe this section can be significantly shortened. Differential activation is an important aspect and should be covered briefly. Some of the information is to in-depth in my opinion and does not add to our current understanding of the MPS system in the horse.

Throughout the manuscript it is unclear if the information provided is evidence found in mice, humans, horses or other species (eg: lines 169-176). It would be helpful to make that more explicit and relevant to findings in equine medicine.

References in certain part of the manuscript do not follow the EVJ reference guidelines; please check carefully.

Specific comments:
Line 95: it is either blocking the CSF-1 receptor or using anti CSF-1 receptor antibodies; blocking anti-CSF-1R treatment does not make sense.

Lines 149-151: authors mention MyD88 dependent and independent pathways first (lines 143-146) and change this nomenclature in lines 149-151. It is beneficial to identify the MyD88 independent pathway in the first sentence as TRIF pathway.

Lines 147-151: only reference 63 describes these pathways in the horse; the other 2 references (64 and 65) refer to mice. Please change or describe the differences with reference to the different species.

Lines 168-212: the description of findings in mice and humans are excessive and can be shortened dramatically (as for example in the peritoneal macrophage section).

Lines 188-190: Despite the absence of CD14 and the role CD14 plays in LPS recognition, even in CD14 lacking mice, LPS is able to activate the TLR4 receptor. The response will be dampened compared to CD14 +/+ mice though. This means that there will be activation, but with a different amplitude as when seen when CD14 would be present (see later comments on LPS recognition).

From line 188 onwards: authors use reference 86 to describe the recognition of LPS by macrophages and other cells. This reference was published before the recognition of TLR4 as the main receptor to recognize LPS.
The interaction of LPS with CD14 and TLR4 and the interplay between CD14 and TLR4, need to be reviewed by the authors and the text adjusted.

Line 281 onwards: how relevant are the cell surface markers found in mice for equine or human health? In other words: is this essential information for our understanding of responses in the equine lung?

Line 311: a reduction “in” equine AM phagocytic capacity

Line 321-322: Although LPS is an important component, Aspergillus fumigatus and other content of hay dust play an equal part in the inflammatory response in lung macrophages (Laan et al 2006).
Reference 149 refers to mice and not horses. Since species differences are important in macrophages responsiveness, conclusions for the horse based on mice studies should be carefully discussed and referenced.

Lines 327-332: TLR2 is not constitutively expressed in the equine lung, but AMs do respond to TLR2 ligands? Can the authors explain this discrepancy?
Authors have not fully described the presence of TLR receptors on different lung cells (including macrophages) as reported by references 151 and 155. For clarity it is important to specify which receptors are expressed where. The next sentence says that TLR9 is also expressed.... suggesting that all TLRs mentioned in the previous sentence are also expressed in all cells mentioned in lines 332-334?

Line 340: “phagocytose”

Line 348-351: What about AMs? They are also capable of directly responding to inflammatory stimuli. Are the authors suggesting that the unique location of PIMs compared to AMs results in a direct effect?

Line 359-368: After reading this paragraph, the remaining feeling is that there are huge differences between the human and equine response through the innate immune system. This questions the horse as an animal model for disease research in humans. The title suggests the horse to be a good model for human innate immunity. In this paragraph/section of the manuscript the authors are describing additional diseases for comparison that in my opinion should be left out.

Line 394: The reference describes the formation of heterodimers between TLR2/1 and TLR2/6 and they recognise different ligands.
For clarity it is important to mention these distinctions in the text. Actually, throughout the manuscript the mention of TLR2 should be coupled to either TLR1 or TLR6 when specific ligands are discussed.

Line 434: Stick to the immune system and not include other diseases

Lines 461-465: It would be beneficial to start this section of the manuscript with these few sentences? Ultimately it is important to stick to the title and focus on the innate immune system.

Line 523: radically in their gene expression: delete “the”

I would like to thank the authors for their revision of the manuscript. In my opinion it is significantly improved. I have just a few minor comments and once addressed by the authors, the manuscript is acceptable for publication.
Line 65: please change into Van Furth and Cohn and others
Lines 191-192: this sentence does not appear to make sense. "whereas IFNA, IFN gamma-induced protein 10 (IP10) and secreted (RANTES, also known as CCL5) induction". There might be something missing in this sentence; I do not understand secreted induction
Line 217: this is the first time FLT3L is mentioned. Should this be spelled out and explained in a bit more detail for clarity?
Line 330: remove the brackets around POI
Line 499-500: the evidence of induced PIMs in humans is indirect. The correct references for this statement are 24-26 and 41 in reference 146. The reference mentioned (146) is a review with the following statement: The mechanisms of induction of PIMs in normal or inflamed lungs are yet to be investigated and understood in a meaningful manner. The statement the authors make is not substantiated by the reference. Yes, PIMs are induced in humans with liver disease, however the evidence is indirect. There is no evidence (at least not in ref 146) that the induction of PIMs leads hypersensitivity of the airways in response to endotoxaemia in humans. Can the others please change this sentence?